Use of a peptide as a therapeutic agent

ABSTRACT

The present invention is directed to the use of the peptide compound Tyr-Pro-Phe-Val-Glu-Pro-Ile-OH as a therapeutic agent for the prophylaxis and/or treatment of cancer, autoimmune diseases, fibrotic diseases, inflammatory diseases, neurodegenerative diseases, infectious diseases, lung diseases, heart and vascular diseases and metabolic diseases. Moreover the present invention relates to pharmaceutical compositions preferably in form of a lyophilisate or liquid buffer solution or artificial mother milk formulation or mother milk substitute containing the peptide Tyr-Pro-Phe-Val-Glu-Pro-Ile-OH optionally together with at least one pharmaceutically acceptable carrier, cryoprotectant, lyoprotectant, excipient and/or diluent.

The present invention is directed to the use of the peptide compoundTyr-Pro-Phe-Val-Glu-Pro-Ile-OH (Beta Casomorphin) as a therapeutic agentfor the prophylaxis and/or treatment of cancer, a neurodegenerativedisease, an infectious disease, an inflammatory disease, an autoimmunedisease, a fibrotic disease, or a heart and vascular disease.

BACKGROUND OF THE INVENTION

The identification of a therapeutic compound effective for theprophylaxis and/or treatment of a disease can be based on the activityof the compound in a biological assay. A biological assay that mimics adisease causative mechanism can be used to test the therapeutic activityof a candidate peptide.

The causative mechanism of many diseases is the over activity of abiological pathway. A peptide that can reduce the activity of thebiological pathway can be effective in the prophylaxis and/or treatmentof the disease caused by the over activity of the biological pathway.Similarly the causative mechanism of many diseases is the overproduction of a biological molecule. A peptide that can reduce theproduction of the biological molecule or block the activity of the overproduced biological molecule can be effective in the prophylaxis and/ortreatment of the disease caused by the over production of the biologicalmolecule.

Conversely, the causative mechanism of many diseases is the underactivity of a biological pathway. A peptide that can increase theactivity of the biological pathway can be effective in the prophylaxisand/or treatment of the disease caused by the under activity of thebiological pathway. Also similarly the causative mechanism of manydiseases is the under production of a biological molecule. A peptidethat can increase the production of the biological molecule or mimic thebiological activity of the under produced biological molecule can beeffective in the prophylaxis and/or treatment of the disease caused bythe under production of the biological molecule.

It is the object of the present invention to provide a compound for theprophylaxis and/or treatment of cancer, autoimmune diseases, fibroticdiseases, inflammatory diseases, neurodegenerative diseases, infectiousdiseases, lung diseases, heart and vascular diseases and metabolicdiseases.

The object of the present invention is solved by the teaching of theindependent claims. Further advantageous features, aspects and detailsof the invention are evident from the dependent claims, the description,and the examples of the present application.

DESCRIPTION OF THE INVENTION

The present invention relates to the use of the peptideTyr-Pro-Phe-Val-Glu-Pro-Ile-OH (Beta Casomorphin), its use as atherapeutic in medicine and for the prophylaxis and/or treatment ofcancer, autoimmune diseases, fibrotic diseases, inflammatory diseases,neurodegenerative diseases, infectious diseases, lung diseases, heartand vascular diseases and metabolic diseases. Also disclosed arepharmaceutical formulations preferably in form of a lyophilisate orliquid buffer solution or artificial mother milk formulation containingthe inventive peptide. The peptide is especially useful for prophylaxisand/or treatment of AIDS, Alzheimer disease, amyotrophic lateralsclerosis, ischemic renal damage, Parkinson's disease, retinitispigmentosa, epilepsy, aplastic anaemia, myelodysplastic syndrome, CD4+T-cell lymphocytopenia, G6PD deficiency, myocardial infarction, stroke,polycystic kidney, acute liver failure, acute tubular necrosis,infertility, streptococcus pneumoniae induced epithelial cell death andinfluenza virus induced cell death and other diseases which aredescribed in the following.

Moreover the present invention relates to a peptide combination of theabove mentioned peptide with the peptide compoundArg-Ser-Gly-Pro-Pro-Gly-Leu-Gln-Gly-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Ala-Ser-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Met-NH₂as well as to pharmaceutical compositions containing said peptidecombination.

Cancer, Tumors, Proliferative Diseases, Malignancies and theirMetastases

The term “cancer” as used herein refers also to tumors, proliferativediseases, malignancies and their metastases. Examples for cancerdiseases are adenocarcinoma, choroidal melanoma, acute leukemia,acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma,basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer,bronchial carcinoma, non-small cell lung cancer (NSCLC), breast cancer,Burkitt's lymphoma, corpus cancer, CUP-syndrome (carcinoma of unknownprimary), colorectal cancer, small intestine cancer, small intestinaltumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelialcancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer,gallbladder cancer, gall bladder carcinomas, uterine cancer, cervicalcancer, cervix, glioblastomas, gynecologic tumors, ear, nose and throattumors, hematologic neoplasias, hairy cell leukemia, urethral cancer,skin cancer, skin testis cancer, brain tumors (gliomas), brainmetastases, testicle cancer, hypophysis tumor, carcinoids, Kaposi'ssarcoma, laryngeal cancer, germ cell tumor, bone cancer, colorectalcarcinoma, head and neck tumors (tumors of the ear, nose and throatarea), colon carcinoma, craniopharyngiomas, oral cancer (cancer in themouth area and on lips), cancer of the central nervous system, livercancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymphnode cancer (Hodgkin's/Non-Hodgkin's), lymphomas, stomach cancer,malignant melanoma, malignant neoplasia, malignant tumorsgastrointestinal tract, breast carcinoma, rectal cancer,medulloblastomas, melanoma, meningiomas, Hodgkin's disease, mycosisfungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renalcell carcinomas, non-Hodgkin's lymphomas, oligodendroglioma, esophagealcarcinoma, osteolytic carcinomas and osteoplastic carcinomas,osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer,plasmocytoma, squamous cell carcinoma of the head and neck (SCCHN),prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma,vaginal cancer, thyroid carcinoma, Schneeberger disease, esophagealcancer, spinalioms, T-cell lymphoma (mycosis fungoides), thymoma, tubecarcinoma, eye tumors, urethral cancer, urologic tumors, urothelialcarcinoma, vulva cancer, wart appearance, soft tissue tumors, softtissue sarcoma, Wilm's tumor, cervical carcinoma and tongue cancer.

The peptides and peptide combination of the present invention was testedusing the assays described in Examples 1-7, 9-17 for their effect asactive therapeutic agents in the prophylaxis and/or treatment of cancer,proliferative diseases, tumors and their metastases.

Infectious Disease

The immune system in higher vertebrates represents the first line ofdefense against various antigens that can enter the vertebrate body,including microorganisms such as bacteria, fungi and viruses that arethe causative agents of a variety of diseases.

Despite large immunization programs, viral infections, such as influenzavirus, human immunodeficiency virus (“HIV”), herpes simplex virus(“HSV”, type 1 or 2), human papilloma virus (“HPV”, type 16 or 18),human cytomegalovirus (“HCMV”) or human hepatitis B or C virus (“HBV”,Type B; “HCV”, type C) infections, remain a serious source of morbidityand mortality throughout the world and a significant cause of illnessand death among people with immune-deficiency associated with aging ordifferent clinical conditions. Although antiviral chemotherapy withcompounds such as amantadine and rimantadine have been shown to reducethe duration of symptoms of clinical infections (i.e., influenzainfection), major side effects and the emergence of drug-resistantvariants have been described. New classes of antiviral agents designedto target particular viral proteins such as influenza neuraminidase arebeing developed. However, the ability of viruses to mutate the targetproteins represents an obstacle for effective treatment with moleculeswhich selectively inhibit the function of specific viral polypeptides.Thus, there is need for new therapeutic strategies to prevent and treatviral infections.

Additionally, there is a need for new therapies for the prevention andtreatment of bacterial infections, especially bacterial infectionscaused by multiple drug resistant bacteria. Currently, bacterialinfections are treated with various antibiotics. Although antibioticshave and can be effective in the treatment of various bacterialinfections, there are a number of limitations to the effectiveness andsafety of antibiotics. For example, some individuals have an allergicreaction to certain antibiotics and other individuals suffer fromserious side effects. Moreover, continued use of antibiotics for thetreatment of bacterial infections contributes to formation ofantibiotic-resistant strains of bacteria.

Another aspect of the present invention is directed to the use of thepeptide or the peptide combination for prophylaxis and/or treatment ofinfectious diseases including opportunistic infections.

Examples of infectious diseases are AIDS, alveolar hydatid disease (AHD,echinococcosis), amebiasis (Entamoeba histolytica infection),Angiostrongylus infection, anisakiasis, anthrax, babesiosis (Babesiainfection), Balantidium infection (balantidiasis), Baylisascarisinfection (raccoon roundworm), bilharzia (schistosomiasis), Blastocystishominis infection (blastomycosis), boreliosis, botulism, Brainerddiarrhea, brucellosis, bovine spongiform encephalopathy (BSE),candidiasis, capillariasis (Capillaria infection), chronic fatiguesyndrome (CFS), Chagas disease (American trypanosomiasis), chickenpox(Varicella-Zoster virus), Chlamydia pneumoniae infection, cholera,Creutzfeldt-Jakob disease (CJD), clonorchiasis (Clonorchis infection),cutaneous larva migrans (CLM) (hookworm infection), coccidioidomycosis,conjunctivitis, Coxsackievirus A16 (hand, foot and mouth disease),cryptococcosis, Cryptosporidium infection (cryptosporidiosis), Culexmosquito (West Nile virus vector), cyclosporiasis (Cyclosporainfection), cysticercosis (neurocysticercosis), Cytomegalovirusinfection, Dengue/Dengue fever, Dipylidium infection (dog and cat fleatapeworm), Ebola virus hemorrhagic fever, encephalitis, Entamoeba coliinfection, Entamoeba dispar infection, Entamoeba hartmanni infection,Entamoeba histolytica infection (amebiasis), Entamoeba poleckiinfection, enterobiasis (pinworm infection), enterovirus infection(non-polio), Epstein-Barr virus infection, Escherichia coli infection,foodborne infection, foot and mouth disease, fungal dermatitis,gastroenteritis, group A streptococcal disease, group B streptococcaldisease, Hansen's disease (leprosy), Hantavirus pulmonary syndrome, headlice infestation (pediculosis), Helicobacter pylori infection,hematologic disease, Hendra virus infection, hepatitis (HCV, HBV),herpes zoster (shingles), HIV Infection, human ehrlichiosis, humanparainfluenza virus infection, influenza, isosporiasis (Isosporainfection), Lassa fever, leishmaniasis, Kala-azar (Kala-azar, LeishmaniaInfection), lice (body lice, head lice, pubic lice), Lyme disease,malaria, Marburg hemorrhagic fever, measles, meningitis, mosquito-bornediseases, Mycobacterium avium complex (MAC) infection, Naegleriainfection, nosocomial infections, nonpathogenic intestinal ameobaeinfection, onchocerciasis (river blindness), opisthorciasis (Opisthorcisinfection), parvovirus infection, plague, Pneumocystis carinii pneumonia(PCP), polio, Q fever, rabies, respiratory syncytial virus (RSV)Infection, rheumatic fever, Rift Valley fever, river blindness(onchocerciasis), rotavirus infection, roundworm infection,salmonellosis, salmonella enteritidis, scabies, shigellosis, shingles,sleeping sickness, smallpox, streptococcal Infection, tapeworm infection(Taenia infection), tetanus, toxic shock syndrome, tuberculosis, ulcers(peptic ulcer disease), valley fever, Vibrio parahaemolyticus infection,Vibrio vulnificus infection, viral hemorrhagic fever, warts, waterborneinfectious diseases, West Nile virus infection (West Nile encephalitis),whooping cough, yellow fever.

Another aspect of the present invention is directed to the use of thepeptide or the peptide combination for prophylaxis and/or treatment ofprion diseases.

Prions are infectious agents which do not have a nucleic acid genome. Itseems that a protein alone is the infectious agent. A prion has beendefined as “small proteinaceous infectious particle which resistsinactivation by procedures that modify nucleic acids”. The discoverythat proteins alone can transmit an infectious disease came as aconsiderable surprise to the scientific community. Prion diseases areoften called “transmissible spongiform encephalopathies”, because of thepost mortem appearance of the brain with large vacuoles in the cortexand cerebellum. Probably most mammalian species develop these diseases.Prion diseases are a group of neurodegenerative disorders of humans andanimals and the prion diseases can manifest as sporadic, genetic orinfectious disorders. Examples of prion diseases acquired by exogenousinfection are bovine spongiform encephalitis (BSE) of cattle and the newvariant of Creutzfeld-Jakob disease (vCJD) caused by BSE as well asscrapie of animals. Examples of human prion diseases include kuru,sporadic Creutzfeldt-Jakob disease (sCJD), familial CJD (fCJD),iatrogenic CJD (iCJD), Gerstmann-Sträussler-Scheinker (GSS) disease,fatal familial insomnia (FFI), and especially the new variant CJD (nvCJDor vCJD).

The name “prion” is used to describe the causative agents which underliethe transmissible spongiform encephalopathies. A prion is proposed to bea novel infectious particle that differs from viruses and viroids. It iscomposed solely of one unique protein that resists most inactivationprocedures such as heat, radiation, and proteases. The lattercharacteristic has led to the term protease-resistant isoform of theprion protein. The protease-resistant isoform has been proposed toslowly catalyze the conversion of the normal prion protein into theabnormal form.

The term “isoform” in the context of prions means two proteins withexactly the same amino acid sequence that can fold into molecules withdramatically different tertiary structures. The normal cellular isoformof the prion protein (PrP^(C)) has a high α-helix content, a low β-sheetcontent, and is sensitive to protease digestion. The abnormal,disease-causing isoform (PrP^(Sc)) has a lower α-helix content, a muchhigher β-sheet content, and is much more resistant to proteasedigestion.

As used herein the term “prion diseases” refers to transmissiblespongiform encephalopathies. Examples for prion diseases comprisescrapie (sheep, goat), transmissible mink encephalopathy (TME; mink),chronic wasting disease (CWD; muledeer, deer, elk), bovine spongiformencephalopathy (BSE; cows, cattles), Creutzfeld-Jacob Disease (CJD),variant CJD (vCJD), sporadic Creutzfeldt-Jakob disease (sCJD), familialCJD (fCJD), iatrogenic CJD (iCJD, Gerstmann-Sträussler-Scheinkersyndrome (GSS), fatal familial insomnia (FFI), and kuru. Preferred areBSE, vCJD, and CJD.

The peptide of the present invention of the present invention weretested using the assays described in Examples 1-7 for their effect asactive therapeutic agents in the prophylaxis and/or treatment ofinfectious diseases and disorders.

Autoimmune Disease

Autoimmune disease refers to any of a group of diseases or disorders inwhich tissue injury is associated with a humoral and/or cell-mediatedimmune response to body constituents or, in a broader sense, an immuneresponse to self. The pathological immune response may be systemic ororgan specific. That is, for example, the immune response directed toself may affect joints, skin, myelin sheath that protects neurons,kidney, liver, pancreas, thyroid, adrenals, and ovaries.

In fact, the list of autoimmune diseases is composed of more than eightydisorders. A few autoimmune diseases such as vitiligo, in which patchesof skin lose pigmentation, are merely annoying. Most others aredebilitating, often progressive with time and eventually fatal. Systemiclupus erythematosus (SLE), for example, is a chronic disease in which10-15% of patients die within a decade of diagnosis, in all but a fewautoimmune diseases, the sex ratio skews towards women. For example, inSLE the ratio of female to male patients is nine to one. In oneparticular case, Hashimoto's disease in which the immune system attacksthe thyroid gland, the ratio is fifty to one.

It has long been known that immune complex formation plays a role in theetiology and progression of autoimmune disease. For example,inflammation in patients with arthritis has long been considered toinvolve phagocytosis by leukocytes of complexes of antigen, antibody andcomplement-immune complexes. However, only now it is being recognizedthat inflammation caused by immune complexes in the joints (arthritis),the kidneys (glomerulonephritis), and blood vessels (vasculitis) is amajor cause of morbidity in autoimmune diseases. Increased immunecomplex formation correlates with the presence of antibodies directed toself or so-called autoantibodies, and the presence of the latter canalso contribute to tissue inflammation either as part of an immunecomplex or unbound to antigen (free antibody). In some autoimmunediseases, the presence of free autoantibody contributes significantly todisease pathology. This has been clearly demonstrated for example in SLE(anti-DNA antibodies), immune thrombocytopenia (antibody responsedirected to platelets), and to a lesser extent rheumatoid arthritis (IgGreactive rheumatoid factor). The important role of immune complexes andfree autoantibodies is further demonstrated by the fact that successfultreatment of certain autoimmune diseases has been achieved by theremoval of immune complexes and free antibody by means of specificimmunoadsorption procedures. For example, the use of an apheresisprocedure in which immune complexes and antibodies are removed bypassage of a patient's blood through an immunoaffinity column wasapproved by the U.S. FDA in 1987 for immune thrombocytopenia (ITP) andin 1999 for rheumatoid arthritis. However, currently there is noapproved method for the treatment of autoimmune diseases whichfacilitates the elimination of immune complexes and autoantibodies byadministration of a drug.

Another aspect of the etiology and progression of autoimmune disease isthe role of proinflammatory cytokines. Under normal circumstances,proinflammatory cytokines such as tumor necrosis factor α (TNFα) andinterleukin-1 (IL-1) play a protective role in the response to infectionand cellular stress. However, the pathological consequences which resultfrom chronic and/or excessive production of TNFα and IL-1 are believedto underlie the progression of many autoimmune diseases such asrheumatoid arthritis, Crohn's disease, inflammatory bowel disease, andpsoriasis. Other proinflammatory cytokines include interleukin-6,interleukin-8, interleukin-17, and granulocyte-macrophage colonystimulating factor.

Naturally occurring CD4+CD25+ regulatory T cells (Tregs) play a criticalrole in the control of periphery tolerance to self-antigens.Interestingly, they also control immune responses to allergens andtransplant antigens. Recent studies in animal models have shown thatadoptive transfer of CD4+CD25+ Tregs can prevent or even cure allergicand autoimmune diseases, and appear to induce transplantation tolerance.Thus, adoptive cell therapy using patient-specific CD4+CD25+ Tregs hasemerged as an individualized medicine for the treatment of inflammatorydisease including allergy, autoimmune disease and transplant rejection.Furthermore, strategies to activate and expand antigen-specificCD4+CD25+ Tregs in vivo using pharmacological agents may represent anovel avenue for drug development.

The interaction of leukocytes with the vessel endothelium to facilitatethe extravasation into the tissue represents a key process of the body'sdefense mechanisms. Excessive recruitment of leukocytes into theinflamed tissue in chronic diseases like autoimmune disorders could beprevented by interfering with the mechanisms of leukocyte extravasation.Significant progress in elucidating the molecular basis of thetrafficking of leukocytes from the blood stream to the extravasculartissue has been achieved that enables new strategies for therapeuticapproaches. The multistep process of leukocyte rolling, firm adhesionand transmigration through the endothelial wall is facilitated by adynamic interplay of adhesion receptors on both leukocytes and onendothelial cells as well as chemokines. In preclinical studies usingvarious animal models, promising results have been obtaineddemonstrating that blocking of adhesion receptors of the selectin andintegrin families improved the inflammation process in models ofulcerative colitis, autoimmune encephalomyelitis or contacthypersensitivity. In addition to the targeting of adhesion receptors byantibodies, small molecules that mimic epitopes of adhesion receptorligands have been developed and successfully applied in animal models.Clinical studies revealed a limited response using antibodies toselectins or leukocyte function-associated antigen 1 (LFA-1) integrinscompared with animal models. However, using humanized antibodies to thealpha 4-integrin subunit significant efficacy has been demonstrated inautoimmune diseases like psoriasis, multiple sclerosis and inflammatorybowel disease.

Examples of autoimmune diseases of the eyes are idiopathicopticus-neuritis, ophthalmia sympathica, anterior uveitis and otheruveitis forms, retina degeneration, and Mooren's ulcer.

Examples of autoimmune diseases of the skin are bullous pemphigoides,chronic urticaria (autoimmune subtype), dermatitis herpetiformis (morbusDuhring), epidermolysis bullosa aquisita (EBA), acquired angioedema,herpes gestationes, hypocomplementemic urticarial vasculitis syndrome(HUVS), linear IgA-dermatosis, and pemphigus.

Examples of hematological autoimmune diseases are autoimmune hemolyticanemia, autoimmune neutropenia, Evans syndrome, inhibitor hemophilia,idiopathic thrombocytopenial purpura (ITP) and pernicious anemia.

Examples of gynecological autoimmune diseases are habitual abortion andinfertility.

Examples of autoimmune diseases of the heart are congenital heart block,idiopathic dilatative cardiomyopathy, peripartum-cardiomyopathy,postcardiotomy syndrome, and postinfarct syndrome (Dressler syndrome).

Examples of autoimmune diseases of the ear, nose and throat are chronicsensorineural hearing loss and morbus Meniere.

Examples of autoimmune diseases of the colon are autoimmune enteropathy,colitis ulcerosa, indeterminant colitis, Crohn's disease andgluten-sensitive enteropathy.

Examples of autoimmune endocrinological autoimmune disorders areautoimmune polyglandulary syndrome type 1, autoimmune polyglandularysyndrome type 2, diabetes mellitus type 1 (IDDM), Hashimoto-thyroiditis,insulin-autoimmune-syndrome (IAS), idiopathic diabetes insipidus,idiopathic hypoparathyroidism, idiopathic Addison's disease andGraves-Basedow disease.

Examples of autoimmune diseases of the liver are autoimmune hepatitis(AIH type 1, 2 and 3), primary biliary cirrhosis (PBC), and primarysclerosing cholangitis.

Example of autoimmune diseases of the lung is Goodpasture's syndrome.

An example of an autoimmune disease of the stomach is chronic atrophic(type A) gastritis.

Examples of neurological autoimmune disorders are Guillain-Barrésyndrome, IgM gammopathy-associated neuropathy, Lambert-Eaton syndrome,Miller-Fisher syndrome, multiple sclerosis, multifocal motoricneuropathy, myasthenia gravis, paraneoplastic neurological syndrome,Rasmussen's encephalitis, and stiff-man syndrome.

Examples of autoimmune diseases of the kidney are anti-TBM-nephritis,Goodpasture's syndrome/anti-GBM-nephritis, IgA-nephropathy, interstitialnephritis, and membrane proliferative glomerulonephritides.

Further diseases that may be caused by an autoimmune reaction are Behcetdisease, chronic fatigue immune dysfunction syndrome (CFIDS), Cogansyndrome I, endometriosis, HELLP syndrome, Bechterew's disease,polymyalgia rheumatica, psoriasis, sarcoidosis and vitiligo.

During the last decade, new biotherapies have been developed for thetreatment of systemic autoimmune diseases. The targets of these newtreatments are all the steps of the immune response. These new therapiesare: B lymphocyte (BL) inhibitors such as anti-CD20 monoclonal antibody,B lymphocyte stimulator (BLyS) antagonists and tolerogens ofpathogenic-antibody secreting LB; inhibitors of the costimulationbetween antigen-presenting cells and T lymphocyte (TL) like monoclonalanti-CD40 ligand antibody or CTLA4-Ig (abatecept); TL antagonists whichcan inhibit the proliferation of autoreactive T cells; cytokineantagonists; chemokine and adhesin antagonists which inhibit traffickingof immunocompetent cells to target organs. These new approaches arebased on a better understanding of the autoimmune response.

The peptide of the present invention of the present invention weretested using the assays described in Examples 14-15 for their effect asactive therapeutic agents in the prophylaxis and/or treatment ofautoimmune diseases and disorders.

Fibrotic Disease

Fibrosis or fibrosis associated disorder affects the liver, epidermis,endodermis, muscle, tendon, cartilage, heart, pancreas, lung, uterus,nervous system, testis, ovary, adrenal gland, artery, vein, colon, smallintestine, biliary tract, or stomach. In a further embodiment, thefibrosis or fibrosis associated disorder is interstitial lung fibrosis.In another embodiment the fibrosis or fibrosis associated disorder isthe result of an infection with schistosoma. In another embodiment thefibrosis or fibrosis associated disorder is the result of wound healing.

Fibrosis is generally characterized by the pathologic or excessiveaccumulation of collagenous connective tissue. Fibrotic diseases anddisorders include, but are not limited to, collagen disease,interstitial lung disease, human fibrotic lung disease (e.g.,obliterative bronchiolitis, idiopathic pulmonary fibrosis, pulmonaryfibrosis from a known etiology, tumor stroma in lung disease, systemicsclerosis affecting the lungs, Hermansky-Pudlak syndrome, coal worker'spneumoconiosis, asbestosis, silicosis, chronic pulmonary hypertension,AIDS associated pulmonary hypertension, sarcoidosis, and the like),fibrotic vascular disease, tubulointerstitial and glomerular fibrosis,myocardial fibrosis, arterial sclerosis, atherosclerosis, varicoseveins, coronary infarcts, cerebral infarcts, myocardial fibrosis,musculoskeletal fibrosis, post-surgical adhesions, human kidney disease(e.g., nephritic syndrome, Alport's syndrome, HIV associatednephropathy, polycystic kidney disease, Fabry's disease, diabeticnephropathy, chronic glomerulonephritis, nephritis associated withsystemic lupus, and the like), cutis keloid formation, progressivesystemic sclerosis (PSS), primary sclerosing cholangitis (PSC), liverfibrosis, liver cirrhosis, renal fibrosis, pulmonary fibrosis, cysticfibrosis, chronic graft versus host disease, scleroderma (local andsystemic), Grave's opthalmopathy, diabetic retinopathy, glaucoma,Peyronie's disease, penis fibrosis, urethrostenosis after a test using acystoscope, inner accretion after surgery, scarring, myelofibrosis,idiopathic retroperitoneal fibrosis, peritoneal fibrosis from a knownetiology, drug induced ergotism, fibrosis incident to benign ormalignant cancer, fibrosis incident to microbial infection (e.g., viral,bacterial, parasitic, fungal, etc.), Alzheimer's disease, fibrosisincident to inflammatory bowel disease (including stricture formation inCrohn's disease and microscopic colitis), fibrosis induced by chemicalor environmental insult (e.g., cancer chemotherapy, pesticides,radiation/cancer radiotherapy), and the like.

Diseases associated with fibrosis include lupus, graft versus hostdisease, scleroderma, systemic sclerosis, scleroderma-like disorders,sine scleroderma, calcinosis, Raynaud's esophageal dysfunction,sclerodactyl), telangiectasiae, hypersensitivity pneumonitis, collagenvascular disease, asthma, pulmonary arterial hypertension,glomerulonephritis, chronic obstructive pulmonary disease, fibrosisfollowing myocardial infarction, central nervous system fibrosisfollowing a stroke or neuro-degenerative diseases (e.g. Alzheimer'sdisease), proliferative vitreoretinopathy (PVR) and arthritis,silicosis, asbestos induced pulmonary fibrosis, acute lung injury andacute respiratory distress syndrome (including bacterial pneumoniainduced, trauma induced, viral pneumonia induced, tuberculosis,ventilator induced, non-pulmonary sepsis induced, and aspirationinduced).

Increased Number of Activated Myofibroblasts in Fibrotic Diseases

The emergence and disappearance of the myofibroblast appears tocorrelate with the initiation of active fibrosis and its resolution,respectively. In addition, the myofibroblast has many phenotypicfeatures, which embody much of the pathologic alterations in fibrotictissue, e.g. lung tissue. These features would seem to argue for animportant role for the myofibroblast in the pathogenesis of fibrosis,e.g. lung fibrosis. Furthermore, the persistence of the myofibroblastmay herald progressive disease, and, conversely, its disappearance maybe an indicator of resolution. This in turn suggests that futuretherapeutic strategies targeting the myofibroblast would be productive.

Patients usually exhibit evidence of active fibrosis with increasednumbers of activated fibroblasts, many of which have the phenotypiccharacteristics of myofibroblasts. At these sites, increased amounts ofextracellular matrix deposition are evident with effacement of thenormal alveolar architecture. Animal model studies show themyofibroblast to be the primary source of type I collagen geneexpression in active fibrotic sites. In vitro studies showdifferentiation of these cells from fibroblasts under the influence ofcertain cytokines but indicate their susceptibility to nitric oxidemediated apoptosis. In addition to promoting myofibroblastdifferentiation, transforming growth factor-β1 (TGF-β1) providesprotection against apoptosis. Thus, this well-known fibrogenic cytokineis important both for the emergence of the myofibroblast and itssurvival against apoptotic stimuli. This is consistent with the criticalimportance of this cytokine in diverse models of fibrosis in varioustissues. In view of these properties, the persistence or prolongedsurvival of the myofibroblast may be the key to understanding whycertain forms of lung injury may result in progressive disease,terminating in end stage disease.

Although pulmonary fibrosis has diverse etiologies, there is a commonfeature characteristic of this process, namely, the abnormal depositionof extracellular matrix that effaces the normal lung tissuearchitecture. A key cellular source of this matrix is the mesenchymalcell population that occupies much of the fibrotic lesion during theactive period of fibrosis. This population is heterogeneous with respectto a number of key phenotypes. One of these phenotypes is themyofibroblast, which is commonly identified by its expression inα-smooth muscle actin and by features that are intermediate between thebona fide smooth muscle cell and the fibroblast. The de novo appearanceof myofibroblasts at sites of wound healing and tissue repair/fibrosisis associated with the period of active fibrosis and is considered to beinvolved in wound contraction. Furthermore, the localization ofmyofibroblasts at sites undergoing active extracellular matrixdeposition suggests an important role for these cells in the genesis ofthe fibrotic lesion.

Increased TGF-β₁ Family Levels in Fibrotic Diseases

The transforming growth factor-β₁ (TGF-β₁) family of proteins has themost potent stimulatory effect on extracellular matrix deposition of anycytokines so far examined. In animal models of pulmonary fibrosisenhanced TGF-β₁ gene expression is temporally and spatially related toincreased collagen gene expression and protein deposition. TGF-β₁antibodies reduce collagen deposition in murine bleomycin-induced lungfibrosis and human fibrotic lung tissue shows enhanced TGF-β₁ gene andprotein expression. Several lines of evidence suggest that TGF-β is acentral regulator of pulmonary fibrosis. Several animal models overexpressing TGF-β showed extensive progressive fibrosis but limitedinflammation, indicating that TGF-β may play a predominant role in theprogression of pulmonary fibrosis. Therapeutic efforts are thereforefocusing on inhibition of TGF-β activity, for instance byanti-TGF-β1-antibodies, or modulators of TGF-β1 such as pirfenidone.Pirfenidone inhibits TGF-β1 gene expression in vivo resulting ininhibition of TGF-β1-mediated collagen synthesis and appears to slowprogression of IPF in patients. Other novel, promising antifibroticagents include relaxin (inhibits TGF-β-mediated overexpression ofcollagen and increases collagenases), suramin (inhibits growth factors),prostaglandin E2 (inhibits collagen production) and lovastatin (blocksformation of granulation tissue by induction of fibroblast apoptosis).

Diseases involving the lung associated with increased levels of TGF-βinclude chronic lung disease of prematurity, idiopathic pulmonaryfibrosis, rapid progressive pulmonary fibrosis, giant-cell interstitialpneumonia, acute rejection after lung transplantation, cytomegaloviruspneumonitis after lung transplantation, bronchiolitis obliterans,asbestosis, coal worker's pneumoconiosis, silicosis, histiocytosis,sarcoidosis, eosinophilic granuloma, scleroderma, systemic lupuserythematosus, lymphangioleiomyomatosis, central fibrosis in pulmonaryadenocarcinoma, cystic fibrosis, chronic obstructive lung disease, andasthma.

Increased TNF-α Levels in Fibrotic Diseases

An important role of tumor necrosis factor-α (TNF-α) in interstitialfibrosis has been established using transgenic mice, which eitheroverexpress or display a deficiency of this cytokine. Micetransgenically modified to overexpress TNF-α develop lung fibrosis. Incontrast, mice null for TNF-α show marked resistance to bleomycininduced fibrosis. TNF-α can stimulate fibroblast replication andcollagen synthesis in vitro, and pulmonary TNF-α gene expression risesafter administration of bleomycin in mice. Soluble TNF-α receptorsreduce lung fibrosis in murine models and pulmonary overexpression ofTNF-α in transgenic mice is characterized by lung fibrosis. In patientswith CFA or asbestosis, bronchoalveolar lavage fluid-derived macrophagesrelease increased amounts of TNF-α compared with controls.

Increased TNF-α may induce fibrosis or fibrosis-associated conditionsaffecting any tissue including, for example, fibrosis of an internalorgan, a cutaneous or dermal fibrosing disorder, and fibrotic conditionsof the eye. Fibrosis of internal organs (e.g., liver, lung, kidney,heart blood vessels, gastrointestinal tract) occurs in disorders such aspulmonary fibrosis, idiopathic fibrosis, autoimmune fibrosis,myelofibrosis, liver cirrhosis, veno-occlusive disease, mesangialproliferative glomerulonephritis, crescentic glomerulonephritis,diabetic nephropathy, renal interstitial fibrosis, renal fibrosis insubjects receiving cyclosporin, allograft rejection, HTV associatednephropathy. Other fibrosis-associated disorders include systemicsclerosis, eosinophilia-myalgia syndrome, and fibrosis-associated CNSdisorders such as intraocular fibrosis. Dermal fibrosing disordersinclude, for example, scleroderma, morphea, keloids, hypertrophic scars,familial cutaneous collagenoma, and connective tissue nevi of thecollagen type. Fibrotic conditions of the eye include conditions such asdiabetic retinopathy, post-surgical scarring (for example, afterglaucoma filtering surgery and after crossed-eyes (strabismus) surgery),and proliferative vitreoretinopathy. Additional fibrotic conditions thatmay be treated by the methods of the present invention may result, forexample, from rheumatoid arthritis, diseases associated with prolongedjoint pain and deteriorated joints; progressive systemic sclerosis,polymyositis, dermatomyositis, eosinophilic fascitis, morphea, Raynaud'ssyndrome, and nasal polyposis.

Increased Matrix Metalloproteases Levels in Fibrotic Diseases

The abnormal extracellular matrix (ECM) remodeling observed in the lungsof patients with interstitial pulmonary fibrosis (IPF) is due, at leastin part, to an imbalance between matrix metalloproteases (MMPs) andtissue inhibitor of metalloproteinases (TIMPs). Normal lung fibroblastsdo not make MMP-9 in vitro, whereas fibroblasts from IPF lungs stronglyexpress MMP-9. In addition, fibroblasts from patients with IPF expressincreased levels of all TIMPs. In this setting, TIMPs may play a role inapoptosis in some cell populations. In vitro studies of alveolarmacrophages obtained from untreated patients with idiopathic pulmonaryfibrosis showed marked increase in MMP-9 secretion compared tomacrophages collected from healthy individuals. In animals models ofbleomycin-induced pulmonary fibrosis MMPs have been shown to be elevatedin bronchoalveolar lavage (BAL) fluid. Indeed, a synthetic inhibitor ofMMP, Batimastat, has been shown to significantly reducebleomycin-induced lung fibrosis, again pointing to the importance ofMMPs in the development of this fibrotic disease in the lung. A numberof studies have shown that the actions of MMPs can result in the releaseof growth factors and cytokines. These profibrotic factors requireproteolytic processing for their activation or release fromextracellular matrix or carrier proteins before they can exert theiractivity. In fact, the proteolytic activity processing of several keyfactors involved in the pathogenesis of pulmonary fibrosis such asinsulin-like growth factor (IGF), TGF-β₁ and TNF-α occur through theactions of MMPs, thereby activating or releasing them from inhibitoryprotein-protein interactions. For example, IGFs in vivo are sequesteredby six high affinity IGF binding proteins (IGFBPs1-6), preventing theirability to interact with IGF receptors. Studies examining adults andchildren IPF and interstitial lung disease show that beside IPF, IGFBP-3and IFPB-2 levels are increased in IPF BAL fluid. MMPs have recentlybeen shown to regulate the cleavage of IGF binding proteins, therebyliberating the complexed ligand to affect IGF actions in target cells.Observations have also shown that the gelatinases, MMP-9 and MMP-2 maybe involved in proteolytic activation of latent TGF-β complexes.Furthermore, the MMP inhibitor Batimastat reduces MMP-9 activity in BALfluid, which was associated with decreased amount of TGF-β and TNF-α.

Pulmonary fibrosis can be an all too common consequence of an acuteinflammatory response of the lung to a host of inciting events. Chroniclung injury due to fibrotic changes can result from an identifiableinflammatory event or an insidious, unknown event. The inflammatoryprocess can include infiltration of various inflammatory cell types,such as neutrophils and macrophages, the secretion of inflammatorycytokines and chemokines and the secretion of matrix remodelingproteinases.

Increased CCL 18 Levels in Fibrotic Diseases

The expression and regulation of cysteine-cysteine (CC) chemokine ligand18 (CCL18), a marker of alternative activation, by human alveolarmacrophages (AMs) is increased in patients with pulmonary fibrosis andcorrelates negatively with pulmonary function test parameters. Thus,CCL18 is an ideal diagnostic marker for pulmonary fibrosis.

The peptide of the present invention of the present invention weretested using the assays described in Examples 14-15 for their effect asactive therapeutic agents in the prophylaxis and/or treatment offibrotic diseases and disorders.

Inflammatory Disease

Inflammation is the final common pathway of various insults, such asinfection, trauma, and allergies to the human body. It is characterizedby activation of the immune system with recruitment of inflammatorycells, production of pro-inflammatory cells and production ofpro-inflammatory cytokines. Most inflammatory diseases and disorders arecharacterized by abnormal accumulation of inflammatory cells includingmonocytes/macrophages, granulocytes, plasma cells, lymphocytes andplatelets. Along with tissue endothelial cells and fibroblasts, theseinflammatory cells release a complex array of lipids, growth factors,cytokines and destructive enzymes that cause local tissue damage.

One form of inflammatory response is neutrophilic inflammation which ischaracterized by infiltration of the inflamed tissue by neutrophilpolymorphonuclear leukocytes (PMN), which are a major component of thehost defense. Tissue infection by extracellular bacteria represents theprototype of this inflammatory response. On the other hand, variousnon-infectious diseases are characterized by extravascular recruitmentof neutrophils. This group of inflammatory diseases includes chronicobstructive pulmonary disease, adult respiratory distress syndrome, sometypes of immune-complex alveolitis, cystic fibrosis, bronchitis,bronchiectasis, emphysema, glomerulonephritis, rheumatoid arthritis,gouty arthritis, ulcerative colitis, certain dermatoses such aspsoriasis and vasculitis. In these conditions neutrophils are thought toplay a crucial role in the development of tissue injury which, whenpersistent, can lead to the irreversible destruction of the normaltissue architecture with consequent organ dysfunction. Tissue damage isprimarily caused by the activation of neutrophils followed by theirrelease of proteinases and increased production of oxygen species.

Chronic obstructive pulmonary disease (COPD) is described by theprogressive development of airflow limitation that is not fullyreversible. Most patients with COPD have three pathological conditions;bronchitis, emphysema and mucus plugging. This disease is characterizedby a slowly progressive and irreversible decrease in forced expiratoryvolume in the first second of expiration (FEVi), with relativepreservation of forced vital capacity (FVC). In both asthma and COPDthere is significant, but distinct, remodeling of airways. Most of theairflow obstruction is due to two major components, alveolar destruction(emphysema) and small airways obstruction (chronic obstructivebronchitis). COPD is mainly characterized by profound mucus cellhyperplasia. Neutrophil infiltration of the patient's lungs is a primarycharacteristic of COPD. Elevated levels of proinflammatory cytokines,like TNF-α, and especially chemokines like interleukin-8 (IL-8) andgrowth-regulated oncogene-α (GRO-α) play a very important role inpathogenesis of this disease. Platelet thromboxane synthesis is alsoenhanced in patients with COPD. Most of the tissue damage is caused byactivation of neutrophils followed by their release ofmetalloproteinases, and increased production of oxygen species.

TNF-α has several biologic activities that are important in homeostasisas well as in pathophysiological conditions. The main sources of TNF-αare monocytes-macrophages, T-lymphocytes and mast cells. The findingthat anti-TNF-α antibodies (cA2) are effective in the treatment ofpatients suffering from rheumatoid arthritis (RA) intensified theinterest to find new TNF-α inhibitors as possible potent medicaments forRA. Rheumatoid arthritis is an autoimmune chronic inflammatory diseasecharacterized by irreversible pathological changes of the joints. Inaddition to RA, TNF-α antagonists are also applicable to several otherpathological conditions and diseases such as spondylitis,osteoarthritis, gout and other arthritic conditions, sepsis, septicshock, toxic shock syndrome, atopic dermatitis, contact dermatitis,psoriasis, glomerulonephritis, lupus erythematosus, scleroderma, asthma,cachexia, chronic obstructive lung disease, congestive heart failure,insulin resistance, lung (pulmonary) fibrosis, multiple sclerosis,Crohn's disease, ulcerative colitis, viral infections and AIDS.

The term “immunoinflammatory disorder” encompasses a variety ofconditions, including autoimmune diseases, proliferative skin diseases,and inflammatory dermatoses. Immunoinflammatory disorders result in thedestruction of healthy tissue by an inflammatory process, dysregulationof the immune system, and unwanted proliferation of cells. Examples ofimmunoinflammatory disorders are acne vulgaris; acute respiratorydistress syndrome; Addison's disease; allergic rhinitis; allergicintraocular inflammatory diseases, antineutrophil cytoplasmic antibody(ANCA)-associated small-vessel vasculitis; ankylosing spondylitis;arthritis, asthma; atherosclerosis; atopic dermatitis; autoimmunehepatitis; autoimmune hemolytic anemia; autoimmune hepatitis; Behcet'sdisease; Bell's palsy; bullous pemphigoid; cerebral ischemia; chronicobstructive pulmonary disease; cirrhosis; Cogan's syndrome; contactdermatitis; COPD; Crohn's disease; Cushing's syndrome; dermatomyositis;diabetes mellitus; discoid lupus erythematosus; eosinophilic fasciitis;erythema nodosum; exfoliative dermatitis; fibromyalgia; focalglomerulosclerosis; focal segmental glomerulosclerosis; giant cellarteritis; gout; gouty arthritis; graft versus host disease; handeczema; Henoch-Schonlein purpura; herpes gestationis; hirsutism;idiopathic cerato-scleritis; idiopathic pulmonary fibrosis; idiopathicthrombocytopenic purpura; immune thrombocytopenic purpura inflammatorybowel or gastrointestinal disorders, inflammatory dermatoses; lichenplanus; lupus nephritis; lymphomatous tracheobronchitis; macular edema;multiple sclerosis; myasthenia gravis; myositis; nonspecific fibrosinglung disease; osteoarthritis; pancreatitis; pemphigoid gestationis;pemphigus vulgaris; periodontitis; polyarteritis nodosa; polymyalgiarheumatica; pruritus scroti; pruritis/inflammation, psoriasis; psoriaticarthritis; pulmonary histoplasmosis; rheumatoid arthritis; relapsingpolychondritis; rosacea caused by sarcoidosis; rosacea caused byscleroderma; rosacea caused by Sweet's syndrome; rosacea caused bysystemic lupus erythematosus; rosacea caused by urticaria; rosaceacaused by zoster-associated pain; sarcoidosis; scleroderma; segmentalglomerulosclerosis; septic shock syndrome; shoulder tendinitis orbursitis; Sjogren's syndrome; Still's disease; stroke-induced brain celldeath; Sweet's disease; systemic lupus erythematosus; systemicsclerosis; Takayasu's arteritis; temporal arteritis; toxic epidermalnecrolysis; transplant-rejection and transplant-rejection-relatedsyndromes; tuberculosis; type-1 diabetes; ulcerative colitis; uveitis;vasculitis; and Wegener's granulomatosis.

As used herein, “non-dermal inflammatory disorders” include, forexample, rheumatoid arthritis, inflammatory bowel disease, asthma, andchronic obstructive pulmonary disease. By “dermal inflammatorydisorders” or “inflammatory dermatoses” is meant an inflammatorydisorder selected from psoriasis, guttate psoriasis, inverse psoriasis,pustular psoriasis, erythrodermic psoriasis, acute febrile neutrophilicdermatosis, eczema, asteatotic eczema, dyshidrotic eczema, vesicularpalmoplantar eczema, acne vulgaris, atopic dermatitis, contactdermatitis, allergic contact dermatitis, dermatomyositis, exfoliativedermatitis, hand eczema, pompholyx, rosacea, rosacea caused bysarcoidosis, rosacea caused by scleroderma, rosacea caused by Sweet'ssyndrome, rosacea caused by systemic lupus erythematosus, rosacea causedby urticaria, rosacea caused by zoster-associated pain, Sweet's disease,neutrophilic hidradenitis, sterile pustulosis, drug eruptions,seborrheic dermatitis, pityriasis rosea, cutaneous kikuchi disease,pruritic urticarial papules and plaques of pregnancy, Stevens-Johnsonsyndrome and toxic epidermal necrolysis, tattoo reactions, Wellssyndrome (eosinophilic cellulitis), reactive arthritis (Reiter'ssyndrome), bowel-associated dermatosis-arthritis syndrome, rheumatoidneutrophilic dermatosis, neutrophilic eccrine hidradenitis, neutrophilicdermatosis of the dorsal hands, balanitis circumscriptaplasmacellularis, balanoposthitis, Behcet's disease, erythema annularecentrifugum, erythema dyschromicum perstans, erythema multiforme,granuloma annulare, hand dermatitis, lichen nitidus, lichen planus,lichen sclerosus et atrophicus, lichen simplex chronicus, lichenspinulosus, nummular dermatitis, pyoderma gangrenosum, sarcoidosis,subcorneal pustular dermatosis, urticaria, and transient acantholyticdermatosis.

By “proliferative skin disease” is meant a benign or malignant diseasethat is characterized by accelerated cell division in the epidermis ordermis. Examples of proliferative skin diseases are psoriasis, atopicdermatitis, nonspecific dermatitis, primary irritant contact dermatitis,allergic contact dermatitis, basal and squamous cell carcinomas of theskin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignantkeratosis, acne, and seborrheic dermatitis. As will be appreciated byone skilled in the art, a particular disease, disorder, or condition maybe characterized as being both a proliferative skin disease and aninflammatory dermatosis. An example of such a disease is psoriasis.

Symptoms and signs of inflammation associated with specific conditionsinclude:

-   -   rheumatoid arthritis:—pain, swelling, warmth and tenderness of        the involved joints; generalized and morning stiffness;    -   insulin-dependent diabetes mellitus-insulitis; this condition        can lead to a variety of complications with an inflammatory        component, including:—retinopathy, neuropathy, nephropathy;        coronary artery disease, peripheral vascular disease, and        cerebrovascular disease;    -   autoimmune thyroiditis:—weakness, constipation, shortness of        breath, puffiness of the face, hands and feet, peripheral edema,        bradycardia;    -   multiple sclerosis:—spasticity, blurry vision, vertigo, limb        weakness, paresthesias;    -   uveoretinitis:—decreased night vision, loss of peripheral        vision;    -   lupus erythematosus:—joint pain, rash, photosensitivity, fever,        muscle pain, puffiness of the hands and feet, abnormal        urinalysis (hematuria, cylinduria, proteinuria),        glomerulonephritis, cognitive dysfunction, vessel thrombosis,        pericarditis;    -   scleroderma:—Raynaud's disease; swelling of the hands, arms,        legs and face; skin thickening; pain, swelling and stiffness of        the fingers and knees, gastrointestinal dysfunction, restrictive        lung disease; pericarditis; renal failure;    -   other arthritic conditions having an inflammatory component such        as rheumatoid spondylitis, osteoarthritis, septic arthritis and        polyarthritis:—fever, pain, swelling, tenderness;    -   other inflammatory brain disorders, such as meningitis,        Alzheimer's disease, AIDS dementia encephalitis:—photophobia,        cognitive dysfunction, memory loss;    -   other inflammatory eye inflammations, such as        retinitis:—decreased visual acuity;    -   inflammatory skin disorders, such as, eczema, other dermatites        (e.g., atopic, contact), psoriasis, burns induced by UV        radiation (sun rays and similar UV sources):—erythema, pain,        scaling, swelling, tenderness;    -   inflammatory bowel disease, such as Crohn's disease, ulcerative        colitis:—pain, diarrhea, constipation, rectal bleeding, fever,        arthritis;    -   asthma:—shortness of breath, wheezing;    -   other allergy disorders, such as allergic rhinitis:—sneezing,        itching, runny nose    -   conditions associated with acute trauma such as cerebral injury        following stroke-sensory loss, motor loss, cognitive loss;    -   heart tissue injury due to myocardial ischemia:—pain, shortness        of breath;    -   lung injury such as that which occurs in adult respiratory        distress syndrome:—shortness of breath, hyperventilation,        decreased oxygenation, pulmonary infiltrates;    -   inflammation accompanying infection, such as sepsis, septic        shock, toxic shock syndrome:—fever, respiratory failure,        tachycardia, hypotension, leukocytosis;    -   other inflammatory conditions associated with particular organs        or tissues, such as:        (i) nephritis (e.g., glomeralonephritis):—oliguria, abnormal        urinalysis;        (ii) inflamed appendix:—fever, pain, tenderness, leukocytosis;        (iii) gout:—pain, tenderness, swelling and erythema of the        involved joint, elevated serum and/or urinary uric acid;        (iv) inflamed gall bladder:—abdominal pain and tenderness,        fever, nausea, leukocytosis;        (v) congestive heart failure:—shortness of breath, rales,        peripheral edema;        (vi) Type II diabetes:—end organ complications including        cardiovascular, ocular, renal, and peripheral vascular disease;        (vii) lung (pulmonary) fibrosis:—hyperventilation, shortness of        breath, decreased oxygenation;        (viii) vascular disease, such as atherosclerosis and        restenosis:—pain, loss of sensation, diminished pulses, loss of        function; and        (ix) alloimmunity leading to transplant rejection:—pain,        tenderness, fever.

Apoptosis

Apoptosis or programmed cell death is defined as a mechanism whichoccurs after sufficient cellular damage. It is characteristicallydifferent from cell necrosis in morphology and biochemistry.

Apoptosis results in the condensation of the nuclues, and the cellshrinks. Visible in apoptotic cells is chromosomal fragmentation due tothe controlled digestion of DNA by apoptosis DNAses. Cytoplasmicblebbing and apoptotic bodies are also seen during apoptosis. The endresult of apoptosis is cell death without inflammation of thesurrounding tissue.

In addition to its importance as a biological phenomenon, defectiveapoptotic processes have been implicated in an extensive variety ofdiseases. Excessive apoptosis causes T-cell depletion in AIDS, Alzheimerdisease, Amyotrophic lateral sclerosis, Ischemic renal damage,Parkinson's disease, Retinitis pigmentosa, Epilepsy, Aplastic anaemia,Myelodysplastic syndrome, CD4+ T-cell lymphocytopenia, G6PD deficiency,Myocardial infarction, Stroke, Polycystic kidney, Acute liver failure,Acute tubular necrosis, infertility, Streptococcus pneumoniae inducedepithelial cell death, Influenza virus induced cell death, whereas aninsufficient amount results in uncontrolled cell proliferation, such ascancer.

Apoptosis is an integral part of tissue development. Development of anorgan or tissue is often preceded by the extensive division anddifferentiation of a particular cell, the resultant mass is then“pruned” into the correct form by apoptosis. Unlike cellular deathcaused by injury, apoptosis results in cell shrinkage and fragmentation.This allows the cells to be efficiently phagocytosed and theircomponents reused without releasing potentially harmful intracellularsubstances into the surrounding tissue.

The process of apoptosis is controlled by a diverse range of cellsignals, which may originate either extracellularly or intracellularly.Extracellular signals may include hormones, growth factors, nitric oxideor cytokines and therefore must either cross the plasma membrane ortransduce to effect a response. These signals may positively ornegatively induce apoptosis; in this context the binding and subsequentinitiation of apoptosis by a molecule is termed positive, whereas theactive repression of apoptosis by a molecule is termed negative.

Intracellular apoptotic signalling is a response initiated by a cell inresponse to stress, and may ultimately result in cell suicide. Thebinding of nuclear receptors by glucocorticoids, heat, radiation,nutrient deprivation, viral infection, and hypoxia are all factors thatcan lead to the release of intracellular apoptotic signals by a damagedcell. Before the actual process of cell death is carried out by enzymes,apoptotic signals must be connected to the actual death pathway by wayof regulatory proteins. This step allows apoptotic signals to eitherculminate in cell death, or be aborted should the cell no longer need todie. Several proteins are involved, however two main methods ofachieving regulation have been identified; targeting mitochondriafunctionality, or directly transducing the signal via adapter proteinsto the apoptotic mechanisms. The whole preparation process requiresenergy and functioning cell machinery.

The mitochondria are essential to multicellular life. Without them, acell ceases to respire aerobically and quickly dies—a fact exploited bysome apoptotic pathways. Apoptotic proteins that target mitochondriaaffect them in different ways; they may cause mitochondrial swellingthrough the formation of membrane pores, or they may increase thepermeability of the mitochondrial membrane and cause apoptotic effectorsto leak out. Nitric oxide (NO) is able to induce apoptosis by helping todissipate the membrane potential of mitochondria and therefore make itmore permeable. Mitochondrial proteins known as SMACs (secondmitochondria-derived activator of caspases) are released into thecytosol following an increase in permeability. SMAC binds to inhibitorof apoptosis proteins (IAPs) and deactivates them, preventing the IAPsfrom arresting the apoptotic process and therefore allowing apoptosis toproceed. IAP also normally suppresses the activity of a group ofcysteine proteases called caspases, which carry out the degradation ofthe cell, therefore the actual degradation enzymes can be seen to beindirectly regulated by mitochondrial permeability.

Although many pathways and signals lead to apoptosis, there is only onemechanism that causes the death of the cell in this process; after theappropriate stimulus has been received by the cell and the necessarycontrols exerted, a cell will undergo the organized degradation ofcellular organelles by activated proteolytic caspases. A cell undergoingapoptosis shows a characteristic morphology that can be observed with amicroscope: Cell shrinkage and rounding due to the breakdown of theproteinaceous cytoskeleton by caspases. The cytoplasm appears dense, andthe organelles appear tightly packed. Chromatin undergoes condensationinto compact patches against the nuclear envelope in a process known aspyknosis, a hallmark of apoptosis. The nuclear envelope becomesdiscontinuous and the DNA inside it is fragmented in a process referredto as karyorrhexis. The nucleus breaks into several discrete chromatinbodies or nucleosomal units due to the degradation of DNA. The cellmembrane shows irregular buds. The cell breaks apart into severalvesicles called apoptotic bodies, which are then phagocytosed.

Apoptosis can occur when a cell is damaged beyond repair, infected witha virus, or undergoing stress conditions such as starvation. DNA damagefrom ionizing radiation or toxic chemicals can also induce apoptosis viathe actions of the tumor-suppressing gene p53. The “decision” forapoptosis can come from the cell itself, from the surrounding tissue, orfrom a cell that is part of the immune system. In these cases apoptosisfunctions to remove the damaged cell, preventing it from sapping furthernutrients from the organism, or to prevent the spread of viralinfection.

Apoptosis also plays a role in preventing cancer; if a cell is unable toundergo apoptosis, due to mutation or biochemical inhibition, it cancontinue dividing and develop into a tumor. For example, infection bypapillomaviruses causes a viral gene to interfere with the cell's p53protein, an important member of the apoptotic pathway. This interferencein the apoptotic capability of the cell plays a critical role in thedevelopment of cervical cancer.

In the healthy organism, the number of cells is kept relatively constantthrough cell death and division. Cells must be replaced when they becomediseased or malfunctioning; but proliferation must be compensated bycell death. This balancing process is part of the homeostasis requiredby living organisms to maintain their internal states within certainlimits.

Homeostasis is achieved when the rate of mitosis (cell division) in thetissue is balanced by cell death. If this equilibrium is disturbed, oneof two potentially fatal disorders occurs: The cells are dividing fasterthan they die, effectively developing a tumor. The cells are dividingslower than they die, which results in a disorder of cell loss. Theorganism must orchestrate a complex series of controls to keephomeostasis tightly controlled, a process that is ongoing for the lifeof the organism and involves many different types of cell signaling.Impairment of any one of these controls can lead to a diseased state;for example, dysregulation of signaling pathway has been implicated inseveral forms of cancer.

The peptide of the present invention of the present invention weretested using the assays described in Examples 1-7, 9-18 for their effectas active therapeutic agents in the prophylaxis and/or treatment ofinflammatory diseases and disorders.

Neurodegenerative Disease

The present invention also relates generally to the fields of neurologyand psychiatry and to methods of protecting the cells of a mammaliancentral nervous system from damage or injury.

Injuries or trauma of various kinds to the central nervous system (CNS)or the peripheral nervous system (PNS) can produce profound andlong-lasting neurological and/or psychiatric symptoms and disorders. Oneform that this can take is the progressive death of neurons or othercells of the central nervous system (CNS), i.e., neurodegeneration orneuronal degeneration.

Neuronal degeneration as a result of, for example; Alzheimer's disease,multiple sclerosis, cerebral-vascular accidents (CVAs)/stroke, traumaticbrain injury, spinal cord injuries, degeneration of the optic nerve,e.g., ischemic optic neuropathy or retinal degeneration and othercentral nervous system disorders is an enormous medical and publichealth problem by virtue of both its high incidence and the frequency oflong-term sequelae. Animal studies and clinical trials have shown thatamino acid transmitters (especially glutamate), oxidative stress andinflammatory reactions contribute strongly to cell death in theseconditions. Upon injury or upon ischemic insult, damaged neurons releasemassive amounts of the neurotransmitter glutamate, which is excitotoxicto the surrounding neurons. Glutamate is a negatively charged amino acidthat is an excitatory synaptic transmitter in the mammalian nervoussystem. Although the concentration of glutamate can reach the millimolarrange in nerve terminals its extracellular concentration is maintainedat a low level to prevent neurotoxicity. It has been noted thatglutamate can be toxic to neurons if presented at a high concentration.The term “excitotoxicity” has been used to describe the cytotoxic effectthat glutamate (and other such excitatory amino acids) can have onneurons when applied at high dosages.

Patients with injury or damage of any kind to the central (CNS) orperipheral (PNS) nervous system including the retina may benefit fromneuroprotective methods. This nervous system injury may take the form ofan abrupt insult or an acute injury to the nervous system as in, forexample, acute neurodegenerative disorders including, but not limitedto; acute injury, hypoxia-ischemia or the combination thereof resultingin neuronal cell death or compromise. Acute injury includes, but is notlimited to, traumatic brain injury (TBI) including, closed, blunt orpenetrating brain trauma, focal brain trauma, diffuse brain damage,spinal cord injury, intracranial or intravertebral lesions (including,but not limited to, contusion, penetration, shear, compression orlaceration lesions of the spinal cord or whiplash shaken infantsyndrome).

In addition, deprivation of oxygen or blood supply in general can causeacute injury as in hypoxia and/or ischemia including, but not limitedto, cerebrovascular insufficiency, cerebral ischemia or cerebralinfarction (including cerebral ischemia or infarctions originating fromembolic occlusion and thrombosis, retinal ischemia (diabetic orotherwise), glaucoma, retinal degeneration, multiple sclerosis, toxicand ischemic optic neuropathy, reperfusion following acute ischemia,perinatal hypoxic-ischemic injury, cardiac arrest or intracranialhemorrhage of any type (including, but not limited to, epidural,subdural, subarachnoid or intracerebral hemorrhage).

Trauma or injury to tissues of the nervous system may also take the formof more chronic and progressive neurodegenerative disorders, such asthose associated with progressive neuronal cell death or compromise overa period of time including, but not limited to, Alzheimer's disease,Pick's disease, diffuse Lewy body disease, progressive supranuclearpalsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Dragersyndrome), chronic epileptic conditions associated withneurodegeneration, motor neuron diseases (amyotrophic lateralsclerosis), multiple sclerosis, degenerative ataxias, cortical basaldegeneration, ALS-Parkinson's-dementia complex of Guam, subacutesclerosing panencephalitis, Huntington's disease, Parkinson's disease,synucleinopathies (including multiple system atrophy), primaryprogressive aphasia, striatonigral degeneration, Machado-Joseph diseaseor spinocerebellar ataxia type 3 and olivopontocerebellar degenerations,bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy(Kennedy's disease), primary lateral sclerosis, familial spasticparaplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease,Tay-Sach's disease, Sandhoff disease, familial spastic disease,Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressivemultifocal leukoencephalopathy, familial dysautonomia (Riley-Daysyndrome) or prion diseases (including, but not limited toCreutzfeld-Jakob disease, Gerstmann-Strussler-Scheinker disease, Kurudisease or fatal familial insomnia).

In addition, trauma and progressive injury to the nervous system cantake place in various psychiatric disorders, including but not limitedto, progressive, deteriorating forms of bipolar disorder orschizoaffective disorder or schizophrenia, impulse control disorders,obsessive compulsive disorder (OCD), behavioral changes in temporal lobeepilepsy and personality disorders.

In one preferred embodiment the compounds of the invention would be usedto provide neuroprotection in disorders involving trauma and progressiveinjury to the nervous system in various psychiatric disorders. Thesedisorders would be selected from the group consisting of;schizoaffective disorder, schizophrenia, impulse control disorders,obsessive compulsive disorder (OCD) and personality disorders.

In addition, trauma and injury make take the form of disordersassociated with overt and extensive memory loss including, but notlimited to, neurodegenerative disorders associated with age-relateddementia, vascular dementia, diffuse white matter disease (Binswanger'sdisease), dementia of endocrine or metabolic origin, dementia of headtrauma and diffuse brain damage, dementia pugilistica or frontal lobedementia, including but not limited to Pick's Disease.

Other disorders associated with neuronal injury include, but are notlimited to, disorders associated with chemical, toxic, infectious andradiation injury of the nervous system including the retina, injuryduring fetal development, prematurity at time of birth, anoxic-ischemia,injury from hepatic, glycemic, uremic, electrolyte and endocrine origin,injury of psychiatric origin (including, but not limited to,psychopathology, depression or anxiety), injury from peripheral diseasesand plexopathies (including plexus palsies) or injury from neuropathy(including neuropathy selected from multifocal, sensory, motor,sensory-motor, autonomic, sensory-autonomic or demyelinatingneuropathies (including, but not limited to Guillain-Barre syndrome orchronic inflammatory demyelinating polyradiculoneuropathy) or thoseneuropathies originating from infections, inflammation, immunedisorders, drug abuse, pharmacological treatments, toxins, trauma(including, but not limited to compression, crush, laceration orsegmentation traumas), metabolic disorders (including, but not limitedto, endocrine or paraneoplastic), Charcot-Marie-Tooth disease(including, but not limited to, type 1a, 1b, 2, 4a or 1-X linked),Friedreich's ataxia, metachromatic leukodystrophy, Refsum's disease,adrenomyeloneuropathy, ataxia-telangiectasia, Djerine-Sottas (including,but not limited to, types A or B), Lambert-Eaton syndrome or disordersof the cranial nerves).

Further indications are cognitive disorders. The term “cognitivedisorder” shall refer to anxiety disorders, delirium, dementia, amnesticdisorders, dissociative disorders, eating disorders, mood disorders,schizophrenia, psychotic disorders, sexual and gender identitydisorders, sleep disorders, somatoform disorders, acute stress disorder,obsessive-compulsive disorder, panic disorder, posttraumatic stressdisorder, specific phobia, social phobia, substance withdrawal delirium,Alzheimer's disease, Creutzfeldt-Jakob disease, head trauma,Huntington's disease, HIV disease, Parkinson's disease, Pick's disease,learning disorders, motor skills disorders, developmental coordinationdisorder, communication disorders, phonological disorder, pervasivedevelopmental disorders, Asperger's disorder, autistic disorder,childhood disintegrative disorder, Rett's disorder, pervasivedevelopmental disorder, attention-deficit/hyperactivity disorder (ADHD),conduct disorder, oppositional defiant disorder, pica, ruminationdisorder, tic disorders, chronic motor or vocal tic disorder, Tourette'sdisorder, elimination disorders, encopresis, enuresis, selective mutism,separation anxiety disorder, dissociative amnesia, depersonalizationdisorder, dissociative fugue, dissociative identity disorder, anorexianervosa, bulimia nervosa, bipolar disorders, schizophreniform disorder,schizoaffective disorder, delusional disorder, psychotic disorder,shared psychotic disorder, delusions, hallucinations, substance-inducedpsychotic disorder, orgasmic disorders, sexual pain disorders,dyspareunia, vaginismus, sexual dysfunction, paraphilias, dyssomnias,breathing-related sleep disorder, circadian rhythm sleep disorder,hypersomnia, insomnia, narcolepsy, dyssomnia, parasomnias, nightmaredisorder, sleep terror disorder, sleepwalking disorder, parasomnia, bodydysmorphic disorder, conversion disorder, hypochondriasis, paindisorder, somatization disorder, alcohol related disorders, amphetaminerelated disorders, caffeine related disorders, cannabis relateddisorders, cocaine related disorders, hallucinogen related disorders,inhalant related disorders, nicotine related disorders, opioid relateddisorders, phencyclidine-related disorder, abuse, persisting amnesticdisorder, intoxication, withdrawal.

The term “bipolar and clinical disorders” shall refer to adjustmentdisorders, anxiety disorders, delirium, dementia, amnestic and othercognitive disorders, disorders usually first diagnosed in infancy(e.g.), childhood, or adolescence, dissociative disorders (e.g.dissociative amnesia, depersonalization disorder, dissociative fugue anddissociative identity disorder), eating disorders, factitious disorders,impulse-control disorders, mental disorders due to a general medicalcondition, mood disorders, other conditions that may be a focus ofclinical attention, personality disorders, schizophrenia and otherpsychotic disorders, sexual and gender identity disorders, sleepdisorders, somatoform disorders, substance-related disorders,generalized anxiety disorder (e.g. acute stress disorder, posttraumaticstress disorder), panic disorder, phobia, agoraphobia,obsessive-compulsive disorder, stress, acute stress disorder, anxietyneurosis, nervousness, phobia, posttraumatic stress disorder,posttraumatic stress disorder (PTSD), abuse, obsessive-compulsivedisorder (OCD), manic depressive psychosis, specific phobias, socialphobia, adjustment disorder with anxious features.

Examples for disorders usually first diagnosed in infancy, childhood, oradolescence are: mental retardation, learning disorders, mathematicsdisorder, reading disorder, disorder of written expression, motor skillsdisorders, developmental coordination disorder, communication disorders,expressive language disorder, phonological disorder, mixedreceptive-expressive language disorder, stuttering, pervasivedevelopmental disorders, Asperger's disorder, autistic disorder,childhood disintegrative disorder, Rett's disorder, pervasivedevelopmental disorder, attention-deficit/hyperactivity disorder (ADHD),conduct disorder, oppositional defiant disorder, feeding disorder ofinfancy or early childhood, pica, rumination disorder, tic disorders,chronic motor or vocal tic disorder, Tourette's syndrome, eliminationdisorders, encopresis, enuresis, selective mutism, separation anxietydisorder, reactive attachment disorder of infancy or early childhood,stereotypic movement disorder.

Examples for substance-related disorders are: alcohol related disorders,amphetamine related disorders, caffeine related disorders, cannabisrelated disorders, cocaine related disorders, hallucinogen relateddisorders, inhalant related disorders, nicotine related disorders,opioid related disorders, psychotic disorder, psychotic disorder,phencyclidine-related disorder, abuse, persisting amnestic disorder,anxiety disorder, persisting dementia, dependence, intoxication,intoxication delirium, mood disorder, psychotic disorder, withdrawal,withdrawal delirium, sexual dysfunction, sleep disorder.

The term “neuroprotection” as used herein shall mean; inhibiting,preventing, ameliorating or reducing the severity of the dysfunction,degeneration or death of nerve cells, axons or their supporting cells inthe central or peripheral nervous system of a mammal, including a human.This includes the treatment or prophylaxis of a neurodegenerativedisease; protection against excitotoxicity or ameliorating the cytotoxiceffect of a compound (for example, a excitatory amino acid such asglutamate; a toxin; or a prophylactic or therapeutic compound thatexerts an immediate or delayed cytotoxic side effect including but notlimited to the immediate or delayed induction of apoptosis) in a patientin need thereof.

The term “a patient in need of treatment with a neuroprotective drug” asused herein will refer to any patient who currently has or may developany of the above syndromes or disorders, or any disorder in which thepatient's present clinical condition or prognosis could benefit fromproviding neuroprotection to prevent the development, extension,worsening or increased resistance to treatment of any neurological orpsychiatric disorder.

The term “treating” or “treatment” as used herein, refers to any indiciaof success in the prevention or amelioration of an injury, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology, or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; or improving a subject's physical or mentalwell-being. The treatment or amelioration of symptoms can be based onobjective or subjective parameters; including the results of a physicalexamination, neurological examination, and/or psychiatric evaluations.

In some embodiments this invention provides methods of neuroprotection.In certain embodiments, these methods comprise administering atherapeutically effective amount of the peptide combination of theinvention to a patient who has not yet developed overt, clinical signsor symptoms of injury or damage to the cells of the nervous system butwho may be in a high risk group for the development of neuronal damagebecause of injury or trauma to the nervous system or because of someknown predisposition either biochemical or genetic or the finding of averified biomarker of one or more of these disorders.

Thus, in some embodiments, the methods and compositions of the presentinvention are directed toward neuroprotection in a subject who is atrisk of developing neuronal damage but who has not yet developedclinical evidence. This patient may simply be at “greater risk” asdetermined by the recognition of any factor in a subject's, or theirfamilies, medical history, physical exam or testing that is indicativeof a greater than average risk for developing neuronal damage.Therefore, this determination that a patient may be at a “greater risk”by any available means can be used to determine whether the patientshould be treated with the methods of the present invention.

Accordingly, in an exemplary embodiment, subjects who may benefit fromtreatment by the methods and the peptide or the peptide combination ofthis invention can be identified using accepted screening methods todetermine risk factors for neuronal damage. These screening methodsinclude, for example, conventional work-ups to determine risk factorsincluding but not limited to: for example, head trauma, either closed orpenetrating, CNS infections, bacterial or viral, cerebrovascular diseaseincluding but not limited to stroke, brain tumors, brain edema,cysticercosis, porphyria, metabolic encephalopathy, drug withdrawalincluding but not limited to sedative-hypnotic or alcohol withdrawal,abnormal perinatal history including anoxia at birth or birth injury ofany kind, cerebral palsy, learning disabilities, hyperactivity, historyof febrile convulsions as a child, history of status epilepticus, familyhistory of epilepsy or any seizure related disorder, inflammatorydisease of the brain including lupis, drug intoxication either direct orby placental transfer, including but not limited to cocaine poisoning,parental consanguinity, and treatment with medications that are toxic tothe nervous system including psychotropic medications.

The determination of which patients may benefit from treatment with aneuroprotective drug in patients who have no clinical signs or symptomsmay be based on a variety of “surrogate markers” or “biomarkers”.

As used herein, the terms “surrogate marker” and “biomarker” are usedinterchangeably and refer to any anatomical, biochemical, structural,electrical, genetic or chemical indicator or marker that can be reliablycorrelated with the present existence or future development of neuronaldamage. In some instances, brain-imaging techniques, such as computertomography (CT), magnetic resonance imaging (MRI) or positron emissiontomography (PET), can be used to determine whether a subject is at riskfor neuronal damage. Suitable biomarkers for the methods of thisinvention include, but are not limited to: the determination by MRI, CTor other imaging techniques, of sclerosis, atrophy or volume loss in thehippocampus or overt mesial temporal sclerosis (MTS) or similar relevantanatomical pathology; the detection in the patient's blood, serum ortissues of a molecular species such as a protein or other biochemicalbiomarker, e.g., elevated levels of ciliary neurotrophic factor (CNTF)or elevated serum levels of a neuronal degradation product; or otherevidence from surrogate markers or biomarkers that the patient is inneed of treatment with a neuroprotective drug.

It is expected that many more such biomarkers utilizing a wide varietyof detection techniques will be developed in the future. It is intendedthat any such marker or indicator of the existence or possible futuredevelopment of neuronal damage, as the latter term is used herein, maybe used in the methods of this invention for determining the need fortreatment with the compounds and methods of this invention.

A determination that a subject has, or may be at risk for developing,neuronal damage would also include, for example, a medical evaluationthat includes a thorough history, a physical examination, and a seriesof relevant bloods tests. It can also include an electroencephalogram(EEG), CT, MRI or PET scan. A determination of an increased risk ofdeveloping neuronal damage or injury may also be made by means ofgenetic testing, including gene expression profiling or proteomictechniques. For psychiatric disorders that may be stabilized or improvedby a neuroprotective drug, e.g., bipolar disorder, schizoaffectivedisorder, schizophrenia, impulse control disorders, etc. the above testsmay also include a present state exam and a detailed history of thecourse of the patients symptoms such as mood disorder symptoms andpsychotic symptoms over time and in relation to other treatments thepatient may have received over time, e.g., a life chart. These and otherspecialized and routine methods allow the clinician to select patientsin need of therapy using the methods and formulations of this invention.In some embodiments of the present invention peptides suitable for usein the practice of this invention will be administered either singly orconcomitantly with at least one or more other compounds or therapeuticagents, e.g., with other neuroprotective drugs or antiepileptic drugs,anticonvulsant drugs. In these embodiments, the present inventionprovides methods to treat or prevent neuronal injury in a patient. Themethod includes the step of; administering to a patient in need oftreatment, an effective amount of one of the peptides disclosed hereinin combination with an effective amount of one or more other compoundsor therapeutic agents that have the ability to provide neuroprotectionor to treat or prevent seizures or epileptogenesis or the ability toaugment the neuroprotective effects of the compounds of the invention.

As used herein the term “combination administration” of a compound,therapeutic agent or known drug with the peptide combination of thepresent invention means administration of the drug and the one or morecompounds at such time that both the known drug and the peptidecombination will have a therapeutic effect. In some cases thistherapeutic effect will be synergistic. Such concomitant administrationcan involve concurrent (i.e. at the same time), prior, or subsequentadministration of the drug with respect to the administration of thepeptide combination of the present invention. A person of ordinary skillin the art would have no difficulty determining the appropriate timing,sequence and dosages of administration for particular drugs and peptidesof the present invention.

The said one or more other compounds or therapeutic agents may beselected from compounds that have one or more of the followingproperties: antioxidant activity; NMDA receptor antagonist activity,augmentation of endogenous GABA inhibition; NO synthase inhibitoractivity; iron binding ability, e.g., an iron chelator; calcium bindingability, e.g., a Ca (II) chelator; zinc binding ability, e.g., a Zn (II)chelator; the ability to effectively block sodium or calcium ionchannels, or to open potassium or chloride ion channels in the CNS of apatient.

The peptide or the peptide combination of the present invention weretested using the assays described in Examples 1-7, 9-18 for their effectas active therapeutic agents in the prophylaxis and/or treatment ofneurodegenerative diseases and disorders.

Heart and Vascular Disease

Heart disease is a general term used to describe many different heartconditions. For example, coronary artery disease, which is the mostcommon heart disease, is characterized by constriction or narrowing ofthe arteries supplying the heart with oxygen-rich blood, and can lead tomyocardial infarction, which is the death of a portion of the heartmuscle. Heart failure is a condition resulting from the inability of theheart to pump an adequate amount of blood through the body. Heartfailure is not a sudden, abrupt stop of heart activity but, rather,typically develops slowly over many years, as the heart gradually losesits ability to pump blood efficiently. Risk factors for heart failureinclude coronary artery disease, hypertension, valvular heart disease,cardiomyopathy, disease of the heart muscle, obesity, diabetes, and/or afamily history of heart failure.

Examples of cardiovascular diseases and disorders are: aneurysm, stableangina, unstable angina, angina pectoris, angioneurotic edema, aorticvalve stenosis, aortic aneurysm, arrhythmia, arrhythmogenic rightventricular dysplasia, arteriosclerosis, arteriovenous malformations,atrial fibrillation, Behcet syndrome, bradycardia, cardiac tamponade,cardiomegaly, congestive cardiomyopathy, hypertrophic cardiomyopathy,restrictive cardiomyopathy, carotid stenosis, cerebral hemorrhage,Churg-Strauss syndrome, diabetes, Ebstein's Anomaly, Eisenmengercomplex, cholesterol embolism, bacterial endocarditis, fibromusculardysplasia, congenital heart defects, heart diseases, congestive heartfailure, heart valve diseases, heart attack, epidural hematoma,hematoma, subdural, Hippel-Lindau disease, hyperemia, hypertension,pulmonary hypertension, cardiac hypertrophy, left ventricularhypertrophy, right ventricular hypertrophy, hypoplastic left heartsyndrome, hypotension, intermittent claudication, ischemic heartdisease, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome,long QT syndrome mitral valve prolapse, moyamoya disease, mucocutaneouslymph node syndrome, myocardial infarction, myocardial ischemia,myocarditis, pericarditis, peripheral vascular diseases, phlebitis,polyarteritis nodosa, pulmonary atresia, Raynaud disease, Sneddonsyndrome, superior vena cava syndrome, syndrome X, tachycardia,Takayasu's arteritis, hereditary hemorrhagic telangiectasia,telangiectasis, temporal arteritis, tetralogy of Fallot, thromboangiitisobliterans, thrombosis, thromboembolism, tricuspid atresia, varicoseveins, vascular diseases, vasculitis, vasospasm, ventricularfibrillation, Williams syndrome, peripheral vascular disease, varicoseveins and leg ulcers, deep vein thrombosis, Wolff-Parkinson-Whitesyndrome.

Vascular diseases are often the result of decreased perfusion in thevascular system or physical or biochemical injury to the blood vessel.

Peripheral vascular disease (PVD) is defined as a disease of bloodvessels often encountered as narrowing of the vessels of the limbs.There are two main types of these disorders, functional disease whichdoesn't involve defects in the blood vessels but rather arises fromstimuli such as cold, stress, or smoking, and organic disease whicharises from structural defects in the vasculature such asatherosclerotic lesions, local inflammation, or traumatic injury. Thiscan lead to occlusion of the vessel, aberrant blood flow, and ultimatelyto tissue ischemia.

One of the more clinically significant forms of PVD is peripheral arterydisease (PAD). PAD is often treated by angioplasty and implantation of astent or by artery bypass surgery. Clinical presentation depends on thelocation of the occluded vessel. For example, narrowing of the arterythat supplies blood to the intestine can result in severe postprandialpain in the lower abdomen resulting from the inability of the occludedvessel to meet the increased oxygen demand arising from digestive andabsorptive processes. In severe forms the ischemia can lead tointestinal necrosis. Similarly, PAD in the leg can lead to intermittentpain, usually in the calf, that comes and goes with activity. Thisdisorder is known as intermittent claudication (IC) and can progress topersistent pain while resting, ischemic ulceration, and even amputation.

Peripheral vascular disease is also manifested in atheroscleroticstenosis of the renal artery, which can lead to renal ischemia andkidney dysfunction.

One disease in which vascular diseases and their complications are verycommon is diabetes mellitus. Diabetes mellitus causes a variety ofphysiological and anatomical irregularities, the most prominent of whichis the inability of the body to utilize glucose normally, which resultsin hyperglycemia. Chronic diabetes can lead to complications of thevascular system which include atherosclerosis, abnormalities involvinglarge and medium size blood vessels (macroangiopathy) and abnormalitiesinvolving small blood vessels (microangiopathy) such as arterioles andcapillaries.

Patients with diabetes mellitus are at increased risk of developing oneor more foot ulcers as a result of established long-term complicationsof the disease, which include impaired nerve function (neuropathy)and/or ischemia. Local tissue ischemia is a key contributing factor todiabetic foot ulceration.

In addition to large vessel disease, patients with diabetes sufferfurther threat to their skin perfusion in at least two additional ways.First, by involvement of the non-conduit arteries, which aredetrimentally affected by the process of atherosclerosis, and secondly,and perhaps more importantly, by impairment of the microcirculatorycontrol mechanisms (small vessel disease). Normally, when a body partsuffers some form of trauma, the body part will, as part of the body'shealing mechanism, experience an increased blood flow. When small vesseldisease and ischemia are both present, as in the case of many diabetics,this natural increased blood flow response is significantly reduced.This fact, together with the tendency of diabetics to form blood clots(thrombosis) in the microcirculatory system during low levels of bloodflow, is believed to be an important factor in ulcer pathogenesis.

Neuropathy is a general term which describes a disease process whichleads to the dysfunction of the nervous system, and is one of the majorcomplications of diabetes mellitus, with no well-established therapiesfor either its symptomatic treatment or for prevention of progressivedecline in nerve function.

The thickening and leakage of capillaries caused by diabetes primarilyaffect the eyes (retinopathy) and kidneys (nephropathy). The thickeningand leakage of capillaries caused by diabetes are also associated withskin disorders and disorders of the nervous system (neuropathy).

The eye diseases associated with diabetes are nonproliferative diabeticretinopathy, proliferative diabetic retinopathy, diabetic maculopathy,glaucoma, cataracts and the like.

Other diseases, although not known to be related to diabetes are similarin their physiological effects on the peripheral vascular system. Suchdiseases include Raynaud syndrome, CREST syndrome, autoimmune diseasessuch as erythematosis, rheumatoid disease, and the like.

As used herein, the term “peripheral vascular diseases” comprises anyperipheral vascular disease including peripheral and autonomicneuropathies. Examples of “peripheral vascular disease” includeperipheral arterial disease, such as chronic arterial occlusionincluding arteriosclerosis, arteriosclerosis obliterans andthromboangiitis obliterans (Buerger's disease), macroangiopathy,microangiopathy, diabetes mellitus, thrombophlebitis, phlebemphraxis,Raynaud's disease, Raynaud's syndrome, CREST syndrome, health hazard dueto vibration, Sudeck's syndrome, intermittent claudication, cold sensein extremities, abnormal sensation in extremities, sensitivity to thecold, Meniere's disease, Meniere's syndrome, numbness, lack ofsensation, anesthesia, resting pain, causalgia (burning pain),disturbance of peripheral circulation function, disturbance of nervefunction, disturbance of motor function, motor paralysis, diabeticperipheral circulation disorder, lumbar spinal canal stenosis, diabeticneuropathy, shock, autoimmune disease such as erythematosis, rheumatoiddisease and rheumatoid arthritis, autonomic neuropathy, diabeticautonomic neuropathy, autonomic imbalance, orthostatic hypotension,erectile dysfunction, female sexual dysfunction, retrograde ejaculation,cystopathy, neurogenic bladder, defective vaginal lubrication, exerciseintolerance, cardiac denervation, heat intolerance, gustatory sweating,diabetic complication, hyperglycemia, hypoglycemia unawareness,hypoglycemia unresponsiveness; glaucoma, neovascular glaucoma, cataract,retinopathy, diabetic retinopathy, diabetic maculopathy, occlusion ofretinal artery, obstruction of central artery of retina, occlusion ofretinal vein, macular edema, aged macular degeneration, aged disciformmacular degeneration, cystoid macular edema, palpebral edema, retinaledema, chorioretinopathy, neovascular maculopathy, uveitis, iritis,retinal vasculitis, endophthalmitis, panophthalmitis, metastaticophthalmia, choroiditis, retinal pigment epithelitis, conjunctivitis,cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar opticneuritis, keratitis, blepharitis, exudative retinal detachment, cornealulcer, conjunctival ulcer, chronic nummular keratitis, Thygesonkeratitis, progressive Mooren's ulcer, damage of skin, skin ulcerincluding foot ulcer, diabetic ulcer, burn ulcer, lower leg ulcer,postoperative ulcer, traumatic ulcer, ulcer after herpes zoster,radiation ulcer, drug induced ulcer, frostbite (cold injury), chilblain,gangrene and sudden gangrene, angina pectoris/variant angiitis, coronaryarteriosclerosis (chronic ischemic heart disease, asymptomatic ischemicheart disease, arteriosclerotic cardiovascular disease), myocardialinfarction, heart failure, congestive heart failure and painlessischemic heart disease, pulmonary edema, hypertension, pulmonaryhypertension; portal hypertension, diabetic nephropathy, decubitus,renal failure.

The peptides of the present invention were tested using the assaysdescribed in Examples 1-7, 9-17 for their effect as active therapeuticagents in the prophylaxis and/or treatment of heart and vasculardiseases and disorders and of diseases and disorders dependent onincreased or decreased angiogenesis.

Rare or Orphan Diseases

Another aspect of the present invention is directed to the use of thepeptide compound or the peptide combination as a therapeutic agent forthe prophylaxis and/or treatment of the following orphan diseases aswell as for the prophylaxis and/or treatment of an autoimmune disease, afibrotic disease, an inflammatory disease, a neurodegenerative disease,an infectious disease, or a heart and vascular disease in patientssuffering from one or more of the following Rare or Orphan Diseases:

ABCD syndrome, AAE, ABSD, ACPS III, ACRP syndrome, ACS, ACTH deficiency,isolated ACTH resistance, ADANE, ADCA, ADCME, ADEM, ADLTE, ADULTsyndrome, AEC syndrome, AGM2, AHDS, AIDS wasting syndrome, ALS, ALSG,AMME syndrome, ANOTHER syndrome, AOA1, AOS, APC, Autoimmunepolyendocrinopathy—candidiasis—ectodermal dystrophy syndrome, APUDoma,AR-CMT, ARC syndrome, ARCA, AREDYLD syndrome, ASD, ASPED, ASPWSCRduplication, ATLD, ATR16, ATRUS syndrome, ATS-MR, AVED Aagenaessyndrome, Aarskog like syndrome, Aarskog-Ose-Pande syndrome,Aarskog-Scott syndrome, Aase syndrome, Aase-Smith syndrome, Abdominalaortic aneurysm, Aberrant left pulmonary artery, Abetalipoproteinemia,Ablepharon macrostomia syndrome, Abruzzo-Erickson syndrome, Acalvaria,Acampomelic campomelic dysplasia, Acanthamoeba keratitis, Acanthocyticdisorder, Acanthocytosis, Acanthosis nigricans, Acatalasemia,Aceruloplasminemia, Achalasia, Achard Thiers syndrome,Ad Acheiropodia,Achondroplasia, Achromatopsia, Acitretin embryofetopathy, Ackermansyndrome, Acoustic neurinoma, Acquired generalized lipodystrophy,Acquired hypoprothrombinemia, Acquired ichthyosis, Acquired idiopathicsideroblastic anaemia, Acquired lipoatrophic diabates, Acquiredprothrombin deficiency, Acrodermatitis enteropathica zinc deficiencytype, Acrodysostosis, Acrodysplasia, Acrofacial dysostosis,Acrokeratoderma, Acrokeratoelastoidosis, Acromelanosis, Acromesomelicdwarfism, Acromicric dysplasia, Acroosteolysis dominant type, Acrorenaldefect—ectodermal dysplasia-diabetes, Acrorenal syndrome, Actinicporokeratosis disseminated superficial, Actinic porokeratosis, AcuteRespiratory Distress Syndrome, Acute basophilic leukaemia, Acuteerythroblastic leukaemia, Acute febrile neutrophilic dermatosis, Acuteinflammatory demyelinating polyradiculoneuropathy (aidp), Acuteinterstitial pneumonia, Acute leukaemia of ambiguous lineage, Acuteleukaemia of indeterminate lineage, Acute liver failure, Acutelymphoblastic leukaemia, Acute medullary lesions, Acute megacaryoblasticleukaemia, Acute monoblastic leukaemia, Acute motor and sensory axonalneuropathy (AMSAN), Acute motor axonal neuropathy (AMAN), Acutemyeloblastic leukaemia, Acute myelodysplasia with myelofibrosis, Acutemyelofibrosis, Acute myeloid leukaemia in Down syndrome, Acutemyelomonocytic leukaemia, Acute myelosclerosis, Acute non lymphoblasticleukaemia, Acute panmyelosis with myelofibrosis, Acute peripheralarterial occlusion, Acute promyelocytic leukaemia, Acutetubulointerstitial nephritis and uveitis syndrome, Adactylia unilateral,Adamantinoma, Adams nance syndrome, Adams-Oliver syndrome, Addison'sdisease, Adenine phosphoribosyltransferase deficiency, Adenosinedeaminase deficiency, Adenosylcobalamin deficiency, Adenovirus infectionin immunocompromised patients, Adenylosuccinase deficiency Adhesivearachnoiditis, Adie syndrome, Adrenal adenoma, Adrenal hyperplasia,Adrenal incidentaloma, Adrenal insufficiency, Adrenocortical carcinoma,Adrenoleukodystrophy, Adrenomyeloneuropathy, Adrenomyodystrophy, AdultOnset Still's disease, Adult T-cell leukaemia/lymphoma, Adult idiopathicneutropenia, Adult neuronal ceroid lipofuscinosis (Kufs disease, CLN4),Adult spinal muscular atrophy, Afibrinogenemia, African tick typhus,African trypanosomiasis, Agammaglobulinemia, Age-related maculardegeneration, Ahn-Lerman-Sagie syndrome, Ahumada-Del Castillo syndrome,Aicardi syndrome, Aicardi-Goutieres syndrome, AIDS, Akaba hayasakasyndrome, Akesson syndrome, Alagille syndrome, Alanine-glyoxylateaminotransferase deficiency (hyperoxaluria type 1), Albers-Schonbergdisease, Albright hereditary osteodystophy, Alcock syndrome, Aldolase Adeficiency, Aldosterone synthase deficiency, Aldred syndrome, Alexanderdisease, Algodystrophy, Alkaptonuria, Alkylglycerone phosphate synthasedeficiency, Allan-Herndon-Dudley syndrome, Allergic bronchopulmonaryaspergillosis, Allgrove syndrome, Alopecia, Alpers syndrome,Alpers-Huttenlocher syndrome, Alpha-thalassemia, Alport syndrome,Alström syndrome, Alternating hemiplegia, Alveolar echinococcosis, Alvesdos santos castello syndrome, Alzheimer disease,Amaurosis-hypertrichosis, Ambras syndrome, Amegacaryocytosis, Amelia,Aminoaciduria, Amoebiasis due to Entamoeba histolytica, Ampola syndrome,Amyloid cardiopathy, Amyloid nephropathy, Amyloid polyneuropathy,Amyloidosis, Amylopectinosis, Amyoplasia congenita, Amyotrophic lateralsclerosis, Amyotrophy fat tissue anomaly, Anemia, Anauxetic dysplasia,Ancylostomiasis, Andermann syndrome, Andersen disease, Aneurysmalsubarachnoid haemorrhage, Angelman syndrome, Angio-osteohypertrophicsyndrome, Angiodysgenetic necrotizing myelopathy, Angioedema,Angiofollicular ganglionic hyperplasia, Angiokeratoma, Angioma andvascular malformation, Angiomatosis systemic cystic seip syndrome,Angioneurotic oedema, Angiostrongyliasis, Anguillulosis, Aniridia,Anisakiasis, Ankylosing spondylarthritis, Ankylostomiasis, Annuloaorticectasia, Anodontia, Anonychia, Anophthalmia—heart and pulmonaryanomalies, Anorchidia, Anorexia nervosa, Anotia, Antenatal Epstein-Barrvirus infection, Anterior horn cell disease, Anti-phospholipid syndrome,Antinolo nieto borrego syndrome, Antiplasmin deficiency, Antithrombindeficiency, Antley-Bixler syndrome, Anyane-Yeboa syndrome, Aortacoarctation, Aorta hypoplasia, Aorta-pulmonary artery fistula, Aorticaneurysm syndrome, due to TGFbeta receptors anomalies, Aorticmalformation, Aortic valve atresia, Aortic valve dysplasia, Aortic valvestenosis, APECED syndrome, Apert syndrome, Aphasia, Apical ballooningsyndrome, Aplasia cutis, Aplastic anaemia, Apnea of infancy (AOI), Apneaof prematurity (AOP), Apo A-I deficiency, Apolipoprotein Al amyloidosis,Apple peel syndrome, Apraxia, Arbovirus fever, Arena syndrome, Areolaratrophy of the macula, Argyria, Argyrophilic grain disease, Arhiniachoanal atresia microphthalmia, Arkless-Graham syndrome, Armfieldsyndrome, Arndt-Gottron disease, Arnold-Chiari malformation, Aromatasedeficiency, Arrhinia, Arrhythmogenic right ventricular dysplasia,Arterial calcification, Arterial duct anomalies, Arterial occlusivedisease, Arterial tortuosity, Arteriohepatic dysplasia, Arthritisjuvenile, Arthrogryposis, Arthroophtalmopathy, Arthropathy, Artssyndrome, Asbestosis, Ascher syndrome, Aseptic abscesses syndrome,Aseptic osteitis, Asherman's syndrome, Aspartylglucosaminidasedeficiency, Asperger syndrome, Aspergillosis, Asphyxiating thoracicdystrophy of the newborn, Astley-Kendall dysplasia, Astrocytoma, Ataxia,Atelencephaly, Atelosteogenesis, Atherosclerosis, Atkin-Flaitz syndrome,Atransferrinemia, Atresia, Atrial cardiomyopathy, Atrial myxoma, Atrialseptal defect, Atrichia, Atrioventricular canal complete—fallottetralogy, Atrophia aerata, Atrophoderma vermiculata, Atypical Molesyndrome, Atypical Werner syndrome, Aughton sloan milad syndrome,Aughton-Hufnagle syndrome, Ausems wittebol post hennekam syndrome,Autism, Autoimmune haemolytic anemia, Autoimmune lymphoproliferativesyndrome, Autoimmune pancreatitits, Axenfeld-Rieger syndrome, Ayazisyndrome, B-cell chronic lymphocytic leukaemia, BAFME, BBB syndrome,X-linked, BCD, BEEC, BES, BIDS syndrome, BOD syndrome, BOFS, BORsyndrome, BOS syndrome, BPD, BRESEK syndrome, BRESHECK syndrome, BRIC,BS, BSCL, BTHS, BTK-deficiency, Babesiosis, Bacterial toxic-shocksyndrome, Bahemuka brown syndrome, Baird syndrome, Balantidiasis,Ballard syndrome, Baller-Gerold syndrome, Ballooning cardiomyopathy,Balo diseases, Bamforth syndrome, Bangstad syndrome, Banti syndrome,Bannayan-Riley-Ruvalcaba syndrome, Barachydactyly type A4, Baraitserburn fixen syndrome, Baraitser-Brett-Piesowicz syndrome, Barakatsyndrome, Barber-Say syndrome, Bardet-Biedl syndrome, Bare lymphocytesyndrome, Barnicoat baraitser syndrome, Barraquer-Simons syndrome,Barrett eosophagus, Barth syndrome, Bartonellosis, Bartsocas-Papassyndrome, Bartter syndrome, Basan syndrome, Bassen-Kornzweig disease,Bassoe syndrome, Battaglia neri syndrome, Batten disease, Baughmansyndrome, Bazex syndrome, Bazex-Dupre-Christol syndrome, Bazopouloukyrkanidou syndrome, Bd syndrome, Beals syndrome, Beals-Hecht syndrome,Bean syndrome, Beare stevenson syndrome, Bechterew syndrome,Beckwith-Wiedemann, Beemer-Ertbruggen syndrome, Behcet disease, Behrsyndrome, Behrens-Baumann-Vogel syndrome, Bell's palsy,Bellini-Chiumello-Rimoldi syndrome, Benallegue Lacete syndrome, Bejel,Bencze syndrome, Bennion-Patterson syndrome, Benson's syndrome,Beradinelli-Seip syndrome, Berdon syndrome, Berger disease, Berktabatznik syndrome, Berlin breakage syndrome, Bernard-soulier syndrome,Berylliosis, Besnier-Boeck-Schaumann disease, Bessel-Hagen disease, Bestdisease, Beta thalassemia, Bethlem myopathy, Bickel-Fanconiglycogenosis, Bickers-Adams syndrome, Bickerstaffs brainstemencephalitis, Bicuspid aortic valve, Biemond syndrome, Biermer disease,Bietti's crystalline dystrophy, Bile acid synthesis defect, Bile ductcancer, Biliary atresia, Biliary inflammatory disease, Bilineal acuteleukaemia, Billard-Toutain-Maheut syndrome, Binder syndrome,Bindewald-Ulmer-Muller syndrome, Binswanger disease, Birt-Hogg-Dubesyndrome, Bixier christian gorlin syndrome, Bjornstad syndrome,Blackfan-Diamond anaemia, Blaichman syndrome, Blake's pouch cyst, Blausyndrome, Blepharophimosis, Blepharoptosis, Blepharospasm, Blethenwenick hawkins syndrome, Bloch-Sulzberger syndrome, Bloom syndrome,Blount disease, Blue Diaper syndrome, Bohring syndrome, Bohring-Opitzsyndrome, Boichis syndrome, Bone disease with defective bonemineralisation, Bone disease with increased bone density, Bone marrowfailure, Bonneau-Beaumont syndrome, Bonnemann-Meinecke-Reich syndrome,Bonnet-Dechaume-Blanc syndrome, Book syndrome, Boomerang dysplasia,Booth haworth dilling syndrome, Borjeson-Forssman-Lehmann syndrome, Borksyndrome, Bornholm eye disease, Bosley-Salih-Alorainy syndrome, Bosmahenkin christiansen syndrome, Bothnia retinal dystrophy,Boucher-Neuhauser syndrome, Bourneville syndrome, Boutonneuse fever,Bouwes Bavinck syndrome, Bowen syndrome, Boyadjiev-Jabs syndrome, Boylandew syndrome, Brachman-de Lange syndrome, Brachydactyly—arterialhypertension, Brachymesophalangy II and V, Brachyolmia, Braddock careysyndrome, Bradyopsia, Brain inflammatory disease, Brain injury, Brainsclerosis, Brauer syndrome, Braun bayer syndrome, Braun-Tinschert,Breast cancer, Brill-Zinsser disease, Brittle bone disease, Brodymyopathy, Bronchial carcinoid tumour, Bronchiectasis, Bronchiolitisobliterans organizing pneumonia, Bronchiolitis obliterans withobstructive pulmonary disease, Bronchogenic cyst, Bronchopulmonarydysplasia, Bronspiegel-Zelnick syndrome, Brooke-Spiegler syndrome,Brown-Vialetto-van Laere syndrome, Bruce winship syndrome, Brucellosis,Bruck syndrome, Brugada syndrome, Brunner-Winter syndrome, Brunzellsyndrome, Bruyn scheltens syndrome, Buckley syndrome, Budd-Chiarisyndrome, Buerger's disease, Bull-Nixon syndrome, Bulldog syndrome,Bulimia, Bullous systemic lupus erythematosus, Buntinx lormans martinsyndrome, Burkitt lymphoma, Burn-McKeown syndrome, Burning Mouthsyndrome, Buschke-Fischer-Brauer syndrome, Buschke-Ollendorff syndrome,Buttiens-Fryns syndrome, C syndrome, CACD, CACH syndrome, CADASIL, CAMAKsyndrome, CAMFAK syndrome, CAMOS syndrome, CANOMAD syndrome, CAPsyndrome, CAPOS syndrome, CAPS (cryopyrin associated periodoc syndrome),CAR syndrome, CATCH 22, CATSHL syndrome, CAVC, CCFDN, CCGE syndrome, CDAtype 1, CDG syndrome, CDGIIc, CDP, CDPD, CEDNIK syndrome, CFC syndrome,CHAND syndrome, CREST syndrome, CRMO, CRV, CSD, CSID, CSWSS syndrome,CVID, Cacchi-Ricci disease, Cafe au lait spots syndrome, Caffey disease,Cahmr syndrome, Calcinosis, Calderon gonzalez cantu syndrome,Calpainopathy, Camera lituania cohen syndrome, Campomelia Cumming type,Camptodactyl), Camurati engelmann disease, Canale-Smith syndrome,Canavan disease, Candidiasis, Cantalamessa baldini ambrosi syndrome,Canthus, Carbohydrate metabolism disorder, Cardiogenital syndrome,Cardiomyopathy, Cardioskeletal myopathy, Carey fineman ziter syndrome,Carnevale canun mendoza syndrome, Carnevale-Hernandez-del Castillosyndrome, Carnevale-Krajewska-Fischetto syndrome, Carney complex,Carney-Stratakis syndrome, Carnosinase deficiency, Carnosinemia,Caroli's disease, Carpal Tunnel syndrome, Carpenter syndrome,Carpenter-Waziri syndrome, Carrington's disease, Carrion disease,Carvajal syndrome, Casamassima-Morton-Nance syndrome, Cassia Stocco dosSantos syndrome, Castleman disease, Castro gago pombo novo syndrome,Catalase deficiency, Cataract, Catel-Manzke syndrome, Cayler syndrome,Celiac disease, Celosomia, Cenani lenz syndactylism, Centralneurocytoma, Cephalopolysyndactyl), Ceramidase deficiency, Cerebellarhypoplasia, Cerebral arteriovenous shunt, Cerebral hemorrhage withamyloidosis, Cerebroretinal vasculopathy, Cfc syndrome, Chagas disease,Chanarin disease, Chandler syndrome, Chang-Davidson-Carlson syndrome,Chaotic atrial tachycardia, Char douglas dungan syndrome, Char syndrome,Charge syndrome, Charlevoix disease, Charlie m syndrome, Chediak-Higashilike syndrome, Cheilitis glandularis, Chemke oliver mallek syndrome,Chemodectoma, Chemy-red-spot myoclonus syndrome, Cherubism, ChiariFrommel syndrome, Chitayat haj chahine syndrome, Chitayat moore delbigio syndrome, Chitayat-Meunier-Hodgkinson syndrome, Chitty hall webbsyndrome, Chitty-Hall-Baraitser syndrome, Cholera, Cholestasis,Cholesteryl ester storage disease, Choline acetyltransferase (ChAT)deficiency, Chondrocalcinosis, Chondrodysplasia, Chondrodystrophy,Chordoma, Choreoacanthocytosis, Chorioretinal atrophy, Choristoma,Choroidal dystrophy, Choroidal sclerosis, Choroideremia,Christ-Siemens-Touraine syndrome, Christian syndrome,Christian-Rosenberg syndrome, Christianson syndrome, Christianson-Fouriesyndrome, Christmas tree syndrome, Chromomycosis, Chronic eosinophilicpneumonia, Chronic fatigue syndrome, Chronic inflammatory demyelinatingpolyneuropathy, Chronic myeloproliferative disease, Chronic neutrophilicleukaemia, Chronic pain requiring intraspinal analgesia, Chronicpneumonitis of infancy, Chronic osteomyelitis, Chronic spinal muscularatrophy, Chudley rozdilsky syndrome, Chudley-Lowry-Hoar syndrome,Churg-Strauss syndrome, Chylomicron retention disease, Ciliarydysentery, Ciliary dyskinesia-bronchiectasis, Cilliers-Beightonsyndrome, Cirrhosis associated cardiac dysfunction, Cirrhoticcardiomyopathy, Clarkson disease, Classical Hodgkin disease, Classicalhomocystinuria, Claude-Bernard-Horner syndrome, ClaytonSmith-Donnaisyndrome, Cleido rhizomelic syndrome, Cleidocranial dysostosis,Cleidocranial dysplasia, Clouston syndrome, Coagulation disorder,Coarctation of aorta, Coats disease, Cobb syndrome, Cocaine poisoning,Cockayne syndrome, Codas syndrome, Coeliac disease, Coenzyme Qcytochrome c reductase deficiency, Coffin syndrome, Coffin-Lowrysyndrome, Coffin-Siris syndrome, Cogan syndrome, Cogan-reese syndrome,Cohen hayden syndrome, Cohen lockood wyborney syndrome, Cohen syndrome,Cole carpenter syndrome, Colitis, Collagen anomaly, Collins popesyndrome, Collins sakati syndrome, Coloboma, Colon cancer, Colonicatresia, Colorado tick encephalitis, Combined pituitary hormonedeficiencies, Complement component deficiency, CongenitalLambert-Eaton-like syndrome, Congenital leptin deficiency, Congenitallobar emphysema, Conjunctival disease, Conjunctival vascular anomaly,Conn syndrome, Connective tissue disease, Conradi-Hunermann-Happlesyndrome, Constrictive bronchiolitis, Cooks syndrome, Cooley anaemia,Cooper-Jabs syndrome, Cormier rustin munnich syndrome, Cornealdystrophy, Cornelia de Lange syndrome, Corneodermatoosseous syndrome,Corneogoniodysgenesis, Coronaro-cardiac fistula, Coronary arterialmalformations, Coronary artery aneurysm, Coronary sinus type ASD,Cortada koussef matsumoto syndrome, Costeff optic atrophy syndrome,Costeff syndrome, Costello syndrome, Cote katsantoni syndrome,Cousin-Walbraum-Cegarra syndrome, Cowchock syndrome,Cowchock-Wapner-Kurtz syndrome, Cowden syndrome, Coxoauricular syndrome,Cramer-Niederdellmann syndrome, Crandall syndrome, Crane heise syndrome,Cranial malformation, Craniopharyngioma, Craniorachischisis,Craniostenosis, Craniosynostosis, Craniotelencephalic dysplasia,Craniotubular syndrome, Creatine deficiency, Creeping disease,Creutzfeldt-Jakob disease, Cri du chat syndrome, Crigler-Najjarsyndrome, Crimean-Congo haemorragic fever (CCHF), Crisponi syndrome,Criss-cross heart, Criswick-Schepens syndrome, Crohn disease, Cromesyndrome, Cronkhite canada syndrome, Cross syndrome, Crouzon disease,Crow-Fukase syndrome, Cryoglobulinaemia mixed, Cryptococcosis,Cryptogenic organizing pneumonia, Cryptophthalmia, Cryptosporidiosis,Culler-Jones syndrome, Currarino triad, Curry-Hall syndrome, Curry-Jonessyndrome, Cushing disease, Cutaneomeningospinal angiomatosis, Cutaneouslupus erythematosus, Cutaneous mastocytoma, Cutaneous mastocytosis,Cutaneous photosensitivity colitis, Cutaneous vasculitis, Cutaneuousmyiasis, Cutis laxa, Cutler bass romshe syndrome, Cyclosporosis,Cystathioninuria, Cystic fibrosis, Cystic hamartoma of lung and kidney,Cystic lymphangioma, Cystic renal disease, Cystinosis, Cystinuria,Cytochrome c oxydase deficiency, Cytomegalovirus (CMV) disease inpatients with impaired cell mediated immunity deemed at risk, Cytopenia,Czeizel brooser syndrome, Czeizel losonci syndrome, D ercole syndrome,D-2-hydroxyglutaricaciduria, D-glycerate dehydrogenase deficiency(hyperoxaluria type 2), D-glycerate kinase deficiency,D-glycericacidemia, DCMA syndrome, DCMD, DEND syndrome, DI-CMT, DIDMOADsyndrome (Diabetes Insipidus—Diabetes Mellitus—Optic Atrophy—Deafness),DIS, DK phocomelia syndrome, DKC, DOOR syndrome, DORY, DTDP1, DYT6, Dasilva syndrome, Dacryocystitis osteopoikilosis, Daentl-Townsend-Siegelsyndrome, Dahlberg-Borer-Newcomer syndrome, Daish hardman lamontsyndrome, Dancing Eye syndrome, Dandy walker malformation, Daneman davymancer syndrome, Danon disease, Darier disease, Darier-Gottron disease,Davenport donlan syndrome, David syndrome, Davies disease, Davis lafersyndrome, De Barsy syndrome, De Hauwere-Leroy-Adriaenssens syndrome, DeSantis-Cacchione syndrome, De Smet-Fabry-Fryns syndrome, De Vaaldisease, De la Chapelle dysplasia, De morsier syndrome, Deafness—smallbowel diverticulosis-neuropathy, Deal barratt dillon syndrome, Degosdisease, Dejerine-Sottas syndrome, Dekaban-Arima syndrome, Delayed graftfunction after organ transplantation, Delleman-Oorthuys syndrome,Dementia associated with a metabolic disease, Dementia associated with aneurodegenerative disease, Dementia associated with an infectiousdisease, Dementia associated with hepatic and renal failure,Demodicidosis, Dendritic cell sarcoma, Dendritic cell tumor, Dengue,Dennis cohen syndrome, Dennis fairhurst moore syndrome, Dense (delta)granule disease, Dent disease, Dentin dysplasia, Denys-Drash syndrome,Der Kaloustian-Jarudi-Khoury syndrome, Der kaloustian mcintosh silversyndrome, Dercum's disease, Dermatofibrosarcoma protuberans,Dermatologic allergic disease, Dermatostomatitis Stevens Johnson type,Desbuquois syndrome, Desminopathy, Desmoid disease, Desmosterolosis,Devic's disease, Devriendt legius fryns syndrome, Devriendt vandenberghefryns syndrome, DiGeorge syndrome, Diabetes, Dialysis-relatedarthropathy, Diaphanospondylodysostosis, Diaphragmatic agenesia,Diaphragmatic spinal muscular atrophy, Diffuse alveolar haemorrhage,Diffuse large B cell lymphoma, Diffuse leiomyomatosis—Alport syndromeX-linked, Diffuse neonatal haemangiomatosis, Dihydropyrimidinuria,Dilated cardiomyopathy with ataxia, Dincsoy-Salih-Patel syndrome, Dinnoshearer weisskopf syndrome, Diomedi bernardi placidi syndrome,Dionisi-Vici-Sabetta-Gambarara syndrome, Diphtheria, Diprosopia, Discoidlupus erythematosus, Discrete fibromuscular subaortic stenosis,Distichiasis-congenital heart defects—peripheral vascular anomalies,Distomatosis, Dobrow syndrome, Donath-Landsteiner syndrome,Donnai-Barrow syndrome, Donohue syndrome, Doose syndrome,Dorfman-chanarin disease, Dowling-Degos disease, Dowling-Degos-Kitamuradisease, Down syndrome, Doyne honeycomb retinal dystrophy (DHRD),Drachtman weinblatt sitarz syndrome, Drash syndrome, Dravet syndrome,Drummond syndrome, Du Pan syndrome, Duane syndrome, Dubin-Johnsonsyndrome, Dubowitz syndrome, Duhring brocq disease, Duker-Weiss-Sibersyndrome, Dunnigan syndrome, Dupont sellier chochillon syndrome,Dyggve-Melchior-Clausen disease, Dykes-Markes-Harper syndrome,Dyschondrosteosis, Dyschromatosis universalis, Dysferlinopathy,Dysfibrinogenemia, Dyskeratosis, Dysmorphic syndrome with connectivetissue involvement, Dysosteosclerosis, Dysostosis, Dysphagia lusoria,Dysplasia, Dysprothrombinemia, Dyssegmental dysplasia glaucoma,Dysspondyloenchondromatosis, Dystoni-like syndrome with paroxysmaldisease, Dystonia, EBD, EBJ, EBS, ECP syndrome, EDS III, EEC syndrome,EEM syndrome, EGE, ENT, ERA, ESS1, Eagle-Barret syndrome, Eales disease,Ebola virus disease, Echinocytic disorder, Ectodermal dysplasia,Ectromelia, Ectropion, Eczema-thrombocytopenia-immunodeficiencysyndrome, Edinburgh malformation syndrome, Edward syndrome,Edwards-Patton-Dilly syndrome, Ehlers-Danlos syndrome, Ehrlichiosis,Eiken syndrome, Eisenmenger syndrome, Elastosis perforans serpiginosa,Elejalde syndrome, Elliott ludman teebi syndrome, Elliptocytosis, EllisVan Creveld syndrome, Ellis yale winter syndrome, Elsching syndrome,Emanuel syndrome, Emery-Dreifuss muscular dystrophy, Emery-Nelsonsyndrome, Empty Sella syndrome, Encephalitis, Encephalomyelitis,Encephalopathy, Enchondromatosis, Endometriosis, Endotheliitis, Engstrom syndrome, Engel congenital myasthenia, Engelhard yatziv syndrome,Enolase deficiency, Enteric anendocrinosis, Enteropathy, Enterovirusantenatal infection, Entropion, Envenomization, Eosinophilicendocarditis, Eosinophilic pneumonia, Ependymoma, Epidermolysis bullosa,Epilepsy, Epiphyseal dysplasia, Episodic ataxia, Epispadias, Epithelialovarian cancer, Epithelioma, Epstein-Barr virus infection, Erdheimdisease, Erdheim-Chester disease, Eronen-Somer-Gustafsson syndrome,Erythema, Erythermalgia, Erythroblastopenia, Erythrocytosis,Erythroderma, Erythrokeratoderma, Erythromelalgia, Escher hirt syndrome,Escobar syndrome, Esophageal adenocarcinoma, Esophageal atresia,Essential cryoglobulinaemia, Essential iris atrophy, Essentialosteolysis, Esthesioneuroblastoma, Estrogen receptor deficiency,Estrogen resistance syndrome, Evans syndrome, Ewing sarcoma, Exnersyndrome, Exostoses, Exsudative retinopathy, Extracutaneous mastocytoma,Extrinsic allergic alveolitis, Eye disease, F syndrome, FAP, FASdeficiency, FCS syndrome, FCU, FENIB, FEOM, FFDD type I, FG syndrome,FLOTCH syndrome, FOP, FOSMN syndrome, FPS/AML syndrome, FRAXA syndrome,FRAXE syndrome, FRAXF syndrome, FSH resistance, Fabry disease, FactorVII deficiency, Factor VIII deficiency, Factor X deficiency, Factor XIdeficiency, Factor XII deficiency, Factor XIII deficiency, Factors II,VII, IX and X, combined deficiency, Fahr syndrome, Fallot complex,Familial LCAT deficiency, Fanconi anaemia, Fanconi ichthyosisdysmorphism, Fanconi syndrome, Fanconi-Bickel disease, Fara-Chlupackovasyndrome, Farber lipogranulomatosis, Farmer's lung disease, Fatalinfantile COX deficiency, Faulk-Epstein-Jones syndrome, Favism,Fazio-Londe disease, Fechtner syndrome, Feigenbaum-Bergeron-Richardsonsyndrome, Feingold syndrome, Felty syndrome, Fenton wilkinson toselanosyndrome, Ferlini-Ragno-Calzolari syndrome, Fernhoff-Blackston-Oakleysyndrome, Fetal cytomegalovirus syndrome, Fetal edema, Fetal leftventricular aneurysm, Fibrinogen disorder, Fibrochondrogenesis,Fibrodysplasia ossificans progressiva, Fibromatosis, Fibromusculardysplasia of arteries, Fibromyalgia, Fibronectin glomerulopathy,Fibrosarcoma, Fibrosing mediastinitis, Fibrosis of extraocular muscles,Fiessinger-Leroy-Reiter's syndrome, Figuera syndrome, Filamin anomaly,Filariasis, Filippi syndrome, Fine-Lubinsky syndrome, Finlay-Markessyndrome, Finucane kurtz scott syndrome, Fitz Hugh Curtis syndrome,Fitzsimmons-Guilbert syndrome, Fitzsimmons-McLachlan-Gilbert syndrome,Fitzsimmons-Walson-Mellor syndrome, Fixed subaortic stenosis, Flegeldisease, Floating-Harbor syndrome, Florid cemento-osseous dysplasia,Flynn aird syndrome, Foix chavany marie syndrome, Foix-Alajouaninesyndrome, Follicular atrophoderma-basal cell carcinoma, Folliculardendritic cell sarcoma, Follicular dyskeratoma, Follicular ichthyosis,Follicular lymphoma, Fontaine-Farriaux-Blanckaert syndrome, Forbesdisease, Formey-Robinson-Pascoe syndrome, Forunculoid myiasis, Fountainsyndrome, Fowler-Christmas-Chapple syndrome, Fox Fordyce disease, Fra-Xsyndrome, Fragile X syndrome, Fragoso cid garcia hernandez syndrome,Franceschetti-Klein syndrome, Francois dyscephalic syndrome, Francoissyndrome, Franek bocker kahlen syndrome, Frank-Ter Haar syndrome,Franklin disease, Fraser like syndrome, Fraser syndrome, Frasiersyndrome, Freeman-Sheldon syndrome, Freiberg's disease, Freire maiapinheiro opitz syndrome, Frey's syndrome, Frias syndrome, Friedsyndrome, Fried-Goldberg-Mundel syndrome, Friedman goodman syndrome,Friedreich ataxia, Froelich's syndrome, Froster-Huch syndrome,Froster-Iskenius-Waterson syndrome, Fructosuria, Frydman-Cohen-Karmonsyndrome, Fryns macrocephaly, Fryns-Aftimos syndrome,Fryns-Hofkens-Fabry syndrome, Fuhrmann-Rieger-de Sousa syndrome, Fukudamiyanomae nakata syndrome, Fukuhara syndrome, Fuqua-Berkovitz syndrome,Furlong syndrome, Furukawa takagi nakao syndrome, G syndrome, G6PDdeficiency, GABA metabolism disease, GAMT deficiency, GAPO syndrome,GIST, GM1 gangliosidosis, GOSHS, GRACILE syndrome, GRF Tumour, GSD, GTN,GVH, Gaisbock syndrome, Galactokinase deficiency, Galactosemia,Galactosialidosis, Galloway syndrome, Galloway-Mowat syndrome, Gamborgnielsen syndrome, Game-Friedman-Paradice syndrome, Gamstorp episodicadynamy, Ganglioglioma, Garcia torres guarner syndrome, Garcia-Luriesyndrome, Gardner silengo wachtel syndrome, Gardner-Morrison-Abbottsyndrome, Garret tripp syndrome, Gastric cancer, Gastroschisis, Gaucherdisease, Gaucher-like disease, Geen sandford davison syndrome, Gelineaudisease, Gemignani syndrome, Gemss syndrome, Genes syndrome,Genochondromatosis, Gerbode defect, Gerhardt syndrome, German syndrome,Gershonibaruch-Leibo syndrome, Gerstmann-Straussler-Scheinker syndrome,Ghosal syndrome, Gianotti Crosti syndrome, Giant cell arteritis, Giantplatelet syndrome, Gilbert syndrome, Gilles de la Tourette syndrome,Gillespie syndrome, Gitelman syndrome, Glanzmann thrombasthenia, Glassbone disease, Glass-Chapman-Hockley syndrome, Glaucoma, Glioblastoma,Glomerular disease, Glomerulonephritis, Glomerulopathy with fibronectindeposits (GFND), Gloomy syndrome, Glucagonoma, Glucocorticoidresistance, Glycogen storage disease, Gms syndrome, Goiter-deafnesssyndrome, Golabi-Rosen syndrome, Goldberg syndrome, Goldberg-Maxwellsyndrome, Goldberg-Shprintzen megacolon syndrome, Goldblatt viljoensyndrome, Goldblatt wallis syndrome, Goldenhar syndrome, Goldmann-Favresyndrome, Goldstein hull syndrome, Goldston syndrome, Gollop syndrome,Gollop wolfgang complex, Goltz syndrome, Goltz-Gorlin syndrome, Gombosyndrome, Gonzales del angel syndrome, Goodman syndrome, Goodpasturesyndrome, Goossens-Devriendt syndrome, Gordon syndrom, Gorham syndrome,Gorham-Stout disease, Gorlin syndrome, Gorlin-Chaudhry-Moss syndrome,Graft rejection after lung transplantation, Graft versus host disease,Graham boyle troxell syndrome, Graham-Cox syndrome, Grand-Kaine-Fullingsyndrome, Grange occlusive arterial syndrome, Grant syndrome,Granulocytic sarcoma, Granulomatous allergic angiitis, Granulomatousinflammatory arthritis, dermatitis, and uveitis, Granulomatous mastitis,Graves' disease, Gray platelet syndrome, Greenberg dysplasia, Greigsyndrome, Greither's disease, Griscelli disease, Grix blankenshippeterson syndrome, Groll hirschowitz syndrome,Gronblad-Strandberg-Touraine syndrome, Grosse syndrome, Grover'sdisease, Growth hormone deficiency, Grubben de cock borghgraef syndrome,Gräsbeck-Imerslund disease, Guam disease, Guanidinoacetatemethyltransferase deficiency, Guibaud-Vainsel syndrome, Guillain-Barrésyndrome, Guizar-Vasquez-Luengas syndrome, GuizarVazquez-Sanchez-Manzanosyndrome, Gunal seber basaran syndrome, Gurrieri-Sammito-Bellussisyndrome, Gusher syndrome, Gynandroblastoma, Gunther disease, HADdeficiency, HAE, HAIRAN syndrome, HANAC syndrome, HARD syndrome(Hydrocephalus-agyria-retinal dysplasia), HCDD, HCL, HDL metabolismdisorder, HEM, HEP, HERNS syndrome, HHE syndrome, HHT, HHV-8, HIDsyndrome, HIGM1, HIT, HMSN 5, HMSNP, HNPCC, HNSCC, HPA-1 deficiency,HPE, HSAN 1, HSD deficiency, HSV encephalitis, HSV keratitis, HUS, HVR,Haas-Robinson syndrome, Haddad syndrome, Haematologic cancers,Haemochromatosis, Haemoglobin disorders, Haemolysis, Haemolytic anaemia,Haemolytic uremic syndrome, Haemorrhagic fever, Haemorrhagiparousthrombocytic dystrophy, Hageman factor deficiency, Hagemoser weinsteinbresnick syndrome, Hailey-Hailey disease, Haim-Munk syndrome, Hairy cellleukaemia, Hajdu-Cheney syndrome, Hal-Berg-Rudolph syndrome, Halalsyndrome, Halal-Setton-Wang syndrome, Hallermam streiff like syndrome,Hallermann-Streiff-Francois syndrome, Hallervorden-Spatz disease,Hamanishi ueba tsuji syndrome, Hamano tsukamoto syndrome, Hamman-Richsyndrome, Hanhart syndrome, Hand Foot Mouth syndrome,Hand-Shuller-Christian disease, Hanot syndrome, Hantavirus pulmonarysyndrome, Hapnes boman skeie syndrome, Happy puppet syndrome, Harboyansyndrome, Hardcastle syndrome, Harding ataxia, Harrod syndrome,Harrod-Keele syndrome, Hartnup disorder, Hartsfield bixler demyersyndrome, Hashimoto struma, Hashimoto-Pritzker syndrome,Haspeslagh-Fryns-Muelenaere syndrome, Hawkinsinuria, Hay wells syndrome,Heart block progressive, Heart-hand syndrome, Heavy chain depositiondisease, Hec syndrome, Hecht scott syndrome, Heckenlively syndrome,Heide syndrome, Heimler syndrome, Heiner syndrome (cow's milkhypersensitivity), Helmerhorst heaton crossen syndrome,Hemangioma-thrombocytopenia syndrome, Hemangiopericytoma, Hematopoietichypoplasia, Hemeralopia, Hemi 3 syndrome,Hemiconvulsion-Hemiplegia-Epilepsy syndrome, Hemifacial hyperplasiastrabismus, Hemihypertrophy intestinal web corneal opacity, Hemimelia,Hemitruncus, Hemochromatosis, Hemoglobin C disease, Hemoglobin Edisease, Hemoglobin H disease, Hemolytic anaemia, Hemophilia,Hemorrhagiparous thrombocytic dystrophy, Hennekam koss de geestsyndrome, Hennekam syndrome, Hennekam-Beemer syndrome, Henoch-Schoenleinpurpura, Hepatic cystic hamartoma, Hepatic fibrosis, Hepatic cancer,Hepatic venoocclusive disease, Hepatitis B re-infection following livertransplantation, Hepatitis, Hepatoblastoma, Hepatocellular adenoma,Hepatocellular carcinoma, Hepatoerythropoeitic porphyria, Hepatoportalsclerosis, Hereditary coproporphyria, Hereditaryendotheliopathy-retinopathy—nephropathy-stroke, Hereditary lymphoedematype I, Hereditary motor and sensory neuropathy, Hereditary vascularretinopathie—Raynaud phenomenon-migraine, Hermansky-Pudlak syndrome,Hernandez fragoso syndrome, Hernandez-Aguirre Negrete syndrome, Herpesvirus infection, Herrmann opitz arthrogryposis syndrome, Hers disease,Hersh-Podruch-Weisskopf syndrome, Herva disease, Heterotaxia,Heterozygous OSMED, Hillig syndrome, Hinman syndrome, Hinson-Pepysdisease, Hipo syndrome, Hirayama disease, Hirschsprung disease,Hirsutism, His bundle tachycardia, Histidine metabolism disorder,Histidinuria renal tubular defect, Histiocytic and dendritic celltumour, Histiocytic sarcoma, Histiocytoid cardiomyopathy, HistiocytosisX, Histoplasmosis, Hittner hirsch kreh syndrome, Hmc syndrome, Hodgkinlymphoma, Hoepffner dreyer reimers syndrome, Hoffman's syndrome, Holmesbenacerraf syndrome, Holmes collins syndrome, Holmes-Gang syndrome,Holoacardius amorphus, Holoprosencephaly, Holt-Oram syndrome, Holzgrevewagner rehder syndrome, Homocarnosinosis, Homocystinuria, Homogentisicacid oxydase deficiency, Hoon hall syndrome, Horner syndrome, Hortondisease, Houlston ironton temple syndrome, House allergic alveolitis,Howard young syndrome, Howell-Evans syndrome, Hoyeraal-Hreidarssonsyndrome, Humeroradial synostosis, Humeroradioulnar synostosis,Humerospinal dysostosis, Hunter carpenter mc donald syndrome, Hunterjurenka thompson syndrome, Hunter syndrome, Hunter-Rudd-Hoffmannsyndrome, Hunter-Thompson-Reed syndrome, Huntington disease, Huriezsyndrome, Hurler syndrome, Hurler-Scheie syndrome, Hutchinson-Gilfordsyndrome, Hutteroth spranger syndrome, Hyaline membrane disease,Hyaluronidase deficiency, Hydatidosis, Hyde-Forster-Mccarthy-Berrysyndrome, Hygroma cysticum, Hyperaldosteronism, Hyperargininemia,Hyperbilirubinemia, Hypercalciuria idiopathic, Hypercholesterolemia,Hyperchylomicronemia, Hypercortisolism, Hyperexplexia, Hyperglycinemia,Hyperimidodipeptiduria, Hyperinsulinism, Hyperkeratosis,Hyperlipidaemia, Hyperlipoproteinemia, Hyperlysinemia,Hypermethioninemia, Hyperornithinemia, Hyperostosis, Hyperoxaluria,Hyperparathyroidism, Hyperphalangism dysmorphy bronchomalacia,Hyperphenylalaninemic embryopathy, Hyperpipecolatemia, Hypersensitivitypneumonitis, Hypertelorism, Hyperthermia, Hyperthyroidism,Hypertrichosis, Hypertrophic neuropathy, Hypertrophic or verrucous lupuserythematosus, Hypertrophic subaortic stenosis, Hypobetalipoproteinemia,Hypobetalipoproteinemia, Hypochondroplasia, Hypocomplementaemicleucocytoclasic vasculitis, Hypodontia, Hypofibrinogenemia, Hypokalemicalkalosis, Hypokeratosis, Hypomyelination, Hypoparathyroidism,Hypopituitarism, Hypoplastic left heart syndrome, Hypoplastic rightheart syndrome, Hypospadias, Hypothalamic hamartoblastoma syndrome,Hypothyroidism, Hypotrichosis, Hypoxanthine guaninephosphoribosyltransferase (HPRT) complete deficiency, I-cell disease,BIDS syndrome, ICCA syndrome, ICE syndrome, ICF syndrome, ICOSdeficiency, IDI, IED, IFAP syndrome, IGDA, IGF-1 deficiency, IGHD, IMAGesyndrome, INAD, INCL, IOMID syndrome, IOSCA, IPEX, IPSID, IRAK4deficiency, ISOD, ITP, IVC stenosis, Ichthyiosis, Idaho syndrome,Idiopathic dystonia DYT1, Idiopathic granulomatous mastitis, Idiopathichypereosinophilic syndrome, Idiopathic infantile arterial calcification,Idiopathic infection caused by BCG or atypical mycobacteria, Idiopathicinterstitial pneumonia, Idiopathic juvenile osteoporosis, Idiopathicmyelofibrosis, Idiopathic obliterative arteriopathy, Idiopathicorthostatic hypotension, Idiopathic pulmonary fibrosis, Idiopathicthrombocytopenic purpura, leshima-Koeda-Inagaki syndrome, Iliumsyndrome, Ilyina amoashy grygory syndrome, Imaizumi kuroki syndrome,Immune thrombocytopaenia, Immunodeficiency, Immunoproliferative smallintestinal disease, Infant respiratory distress syndrome,Insulin-resistance syndrome, Insulinoma, Interdigitating dendritic cellsarcoma, Intermediate DEND syndrome, Intermediate spinal muscularatrophy, Internal carotid agenesis, Interstitial cystitis, Interstitialgranulomatous dermatitis with arthritis, Interstitial pneumonia,Interventricular septum aneurysm, Intestinal atresia multiple,Intestinal epithelial dysplasia, Intestinal hypomagnesemia withsecondary hypocalcemia, Intestinal lipodystrophy, Intestinal lipophagicgranulomatosis, Intestinal lymphangiectasia, Intestinalpseudoobstruction, Intracerebral haemorrhage, Intracranial aneurysms,Intracranial arterioveinous malformation, Inverse Marcus-Gunnphenomenon, Iridocorneal endothelial syndrome, Iridogoniodysgenesis,Irons-Bhan syndrome, Irritable bowel syndrome, Isaac's syndrome, Isaacsmertens syndrome, Ischaemic brain injury, Ischemia/perfusion injuryassociated with solid organ transplantation procedure, Ischio-vertebraldysplasia, Iso-Kikuchi syndrome, Isosporiasis, Isotretinoin syndrome,Isotretinoin-like syndrome, Isovaleric acidemia, Itin syndrome, Itohypomelanosis, Ivemark syndrome, JAE, JWS, Jackson-Barr syndrome,Jackson-Weiss syndrome, Jacobs syndrome, Jacobsen syndrome, Jaffecampanacci syndrome, Jaffe-Lichtenstein disease, Jagell holmgren hofersyndrome, Jalili syndrome, Jancar syndrome, Japanese encephalitis,Jarcho-Levin syndrome, Jaw-Winking syndrome, Jensen syndrome,Jequier-Kozlowski syndrome, Jervell and Lange-Nielsen syndrome, Jeunesyndrome, Job syndrome, Johanson-Blizzard syndrome, Johnson syndrome,Johnson-McMillin syndrome, Johnson-Munson syndrome,Johnston-Aarons-Schelley syndrome, Jones syndrome, Jorgenson lenzsyndrome, Joubert syndrome, Joubert-Boltshauser syndrome, Juberg haywardsyndrome, Juberg-Marsidi syndrome, Judge misch wright syndrome, JumpingFrenchman of Maine, Jung wolff back stahl syndrome, Juvenile chronicmyelomonocytic leukaemia, Juvenile gastrointestinal polyposis, Juvenileglaucoma, Juvenile hemochromatosis, Juvenile hyaline fibromatosis,Juvenile idiopathic arthritis, Juvenile macular degeneration, Juvenilemyelomonocytic leukaemia, Juvenile polyposis syndrome (JPS), Juveniletemporal arteritis, KBG syndrome, KBG-like syndrome, KID syndrome,Kabuki syndrome, Kaeser syndrome, Kahler's disease, Kaler garrity sternsyndrome, Kallin syndrome, Kallmann syndrome, Kalyanaraman syndrome,Kanzaki disease, Kaplan-Plauchu-Fitch syndrome, Kaplowitz-Bodurthasyndrome, Kaposi's sarcoma, Kaposiform hemangioendothelioma,Kapur-Toriello syndrome, Karandikar-Maria-Kamble syndrome, Karschneugebauer syndrome, Kartagener syndrome, Kasabach-Merritt syndrome,Kashani-Strom-Utley syndrome, Kasznica carlson coppedge syndrome,Katsantoni papadakou lagoyanni syndrome, Kaufman-Mckusick syndrome,Kawasaki disease, Kawashima syndrome, Kawashima-Tsuji syndrome,Kearns-Sayre syndrome, Kelley-Seegmiller syndrome, Kelly-Kirson-Wyattsyndrome, Kennedy disease, Kennedy-Teebi syndrome, Kennerknechtsyndrome, Kenny syndrome, Kenny-Caffey syndrome, Kenya tick-bite fever,Keratinisation disorder associated with genetic eye disease, Keratitis,Keratoacanthoma, Keratoconus, Keratoderma, Keratosis, Kerion celsi,Kersey syndrome, Ketoacidosis, Ketoaciduria, Ketolysis disorder, Keutelsyndrome, KGB syndrome, Khalifa-Graham syndrome, Kienbock disease,Kikuchi disease, Kikuchi-Fujimoto disease, Kimura disease,King-Denborough syndrome, Kinsbourne syndrome, Klatskin tumour,Klein-Waardenburg syndrome, Kleine-Levin syndrome, Kleiner holmessyndrome, Klinefelter syndrome, Klippel-Feil malformation,Klippel-Trenaunay syndrome, Kluver-Bucy syndrome, Kniest dysplasia,Knobloch layer syndrome, Kocher-Debre-Semelaigne syndrome, Kohler'sdisease, Kohlschutter-Tonz syndrome, Kok disease, Komar syndrome,Konigsmark knox hussels syndrome, Kopysc barczyk krol syndrome, Kosenowsyndrome, Kostmann syndrome, Kosztolanyi syndrome, Koussef nicholssyndrome, Kousseff syndrome, Kowarski syndrome, Kozlowski brown hardwicksyndrome, Kozlowski massen syndrome, Kozlowski ouvrier syndrome,Kozlowski tsuruta syndrome, Kozlowski-Krajewska syndrome, Krabbedisease, Krasnow-Qazi syndrome, Krauss herman holmes syndrome, Kudotamura fuse syndrome, Kugelberg-Welander disease, Kumar-Levick syndrome,Kunze riehm syndrome, Kurczynski-Casperson syndrome, Kuskokwim disease,Kuzniecky syndrome, Kynureninase deficiency, Kyphomelic dysplasia,Kyphosis brachyphalangy optic atrophy, Kussmaul-Maier disease, L1syndrome, L-2-hydroxyglutaricaciduria, LADD syndrome, LBSL, LBWCsyndrome, LCAD, LCAT deficiency, LCCS, LCDD, LCH, LCHAD deficiency, LDD,LEOPARD syndrome, LGMD, LHCDD, LIG4 syndrome, LMS, LORD, LPI, Labandsyndrome, Lachiewicz sibley syndrome, Lactate dehydrogenase deficiency,Lactic acidosis, Lactotroph adenoma, Ladda zonana ramer syndrome, Laforadisease, Laing distal myopathy, Lambdoid synostosis, Lambert syndrome,Lambert-Eaton myasthenic syndrome, Lamellar ichthyosis, Laminopathy,Landau-Kleffner syndrome (LKS), Landing disease, Landouzy-Dejerinemyopathy, Langer-Giedion syndrome, Langerhans cell granulomatosis,Langerhans cell histiocytosis, Langerhans cell sarcoma, Laparoschisis,Laplane fontaine lagardere syndrome, Laron syndrome, Larsen syndrome,Larsen-like syndrome, Laryngeal abductor paralysis, Laryngo onychocutaneous syndrome, Laryngo-tracheo-esophageal cleft pulmonaryhypoplasia, Lassa fever, Lassueur-Graham-Little syndrome, Late infantileneuronal ceroid lipofuscinosis, Late onset sepsis in premature infants,Lathosterolosis, Laubry-pezzi syndrome, Launois-Bensaudeadenolipomatosis, Laurence-Moon syndrome, Laurin-Sandrow syndrome,Lawrence syndrome, Lawrence-Seip syndrome, Laxova-Opitz syndrome, LeMerrer syndrome, Le marec bracq picaud syndrome, Leao-da Silva syndrome,Learman syndrome, Leber ‘plus’ disease, Leber congenital amaurosis,Leber miliary aneurysm, Left renal vein entrapment syndrome, Leftventricular hypertrabeculation, Left ventricular noncompaction,Legg-Calve-Perthes disease, Legionellosis, Legionnaires' disease,Leichtman-Wood-Rohn syndrome, Leifer lai buyse syndrome, Leigh disease,Leiner disease, Leiomyomatosis of esophagus cataract hematuria,Leiomyomatosis, Leiomyosarcoma, Leipala kaitila syndrome, Leishmaniasis,Leisti-Hollister-Rimoin syndrome, Lemierre syndrome, Lenegre disease,Lennox-Gastaut syndrome, Leprechaunism, Leprosy, Leptospirosis, Leripleonosteosis, Leri-Weill syndrome, Lesch-Nyhan syndrome, Lethalarthrogryposis with anterior horn cell disease (LAAHD), Lethalchondrodysplasia moerman type, Lethal congenital contracture syndrome,Lethal osteosclerotic bone dysplasia, Letterer-Siwe disease, Leucinosis,Leukaemia, Leukocyte adhesion deficiency (LAD), Leukodystrophy,Leukoencephalopathy, Leukonychia totalis, Leukotriene C4 (LTC4) synthasedeficiency, Levic stefanovic nikolic syndrome, Levine-Critchleysyndrome, Levocardia, Levy-Hollister syndrome, Levy-Yeboa syndrome,Lewis-Pashayan syndrome, Lewis-Sumner syndrome, Lewy body dementia,Leydig cell hypoplasia, Lhermitte-Duclos disease, Li-Fraumeni syndrome,Lichen, Lichstenstein syndrome, Liddle syndrome, Lindsay-Burn syndrome,Linear hamartoma syndrome, Linitis plastica, Lip-pit syndrome, Lipidstorage disease, Lipodystrophy, Lipodystrophy-HIV related, Lipoedema,Lipoid proteinosis, Lipomatosis, Lipoprotein metabolism disease,Liposarcoma, Lisker-Garcia-Ramos syndrome, Lissencephaly, Listeriosis,Little syndrome, Lobar atrophy of brain, Lobstein disease, Lobster-clawdeformity, Localized Castleman disease, Localized scleroderma, Locked-insyndrome, Loeffler's endocarditis, Loeys-Dietz syndrome, Loffredocennamo cecio syndrome, Logic syndrome, Loiasis, Long QT syndrome,Longman-Tolmie syndrome, Loose anagen syndrome, Lopes gorlin syndrome,Lopes marques de faria syndrome, Lopez-Hernandez syndrome, Lou-Gehrigdisease, Louis-Bar syndrome, Lowe kohn cohen syndrome, Loweoculocerebrorenal syndrome, Lowe syndrome, Lower mesodermal defects,Lown-Ganong-Levine syndrome, Lowry syndrome, Lowry-MacLean syndrome,Lowry-Yong syndrome, Lubani-Al Saleh-Teebi syndrome, Lubinsky syndrome,Lubs-Arena Syndrome, Lucey driscoll syndrome, Lucky gelehrter syndrome,Lujan-Fryns syndrome, Lunatomalacia, Lundberg syndrome, Lung agenesisheart defect thumb anomalies, Lung cancer small cell, Lung fibrosis,Lupus erythematosus, Lurie kletsky syndrome, Luteinizing hormonereleasing hormone deficiency with ataxia, Lutz-Richner-Landolt syndrome,Lyell syndrome, Lyme borreliosis, Lyme disease,Lymphangioleiomyomatosis, Lymphangioma, Lymphatic filariasis, Lymphaticmalformation, Lymphedema, Lymphocyte apoptosis anomaly,Lymphocyte-depleted classical hodgkin lymphoma, Lymphocyte-richclassical hodgkin lymphoma, Lymphocytic colitis, Lymphoid interstitialpneumonia, Lymphomatoid granulomatosis, Lymphoproliferative diseaseassociated with primary immune disease, Lynch lee murday syndrome, Lynchsyndrome, Lyngstadaas syndrome, Lysosomal disease, Lytico-bodig disease,M-CMTC, M/SCHAD, MAD, MADSAM, MAE, MALT lymphoma, MASA syndrome, MCA,MCAD deficiency, MCOPSI, MDCIA, MEB (Muscle-Eye-Brain) syndrome, MEHMOsyndrome, MELAS, MEN1, MEN2, MERRF syndrome, MGA type I, MHBDdeficiency, MIDD, MIRAS, MMEP syndrome, MMND, MNGIE syndrome, MOBAsyndrome, MOCOD, MODY syndrome, MORM syndrome, MPPH syndrome, MPS, MRGH,MRKH syndrome, MRXS7, MSA, MTHFR deficiency, MVA syndrome, MYH9, MacDuffie's syndrome, Mac dermot winter syndrome, Maccario mena syndrome,Macdermot-Patton-Williams syndrome, Machado-Joseph disease, Maciasflores garcia cruz rivera syndrome, Mackay shek carr syndrome,Macroglossia, Macrophage or histiocytic tumour, Macrophagic activationsyndrome, Macrophagic myofasciitis, Macrothrombocytopenia with leukocyteinclusions, Macular amyloidosis, Macular dystrophy, Macular edema,Madelung's disease, Madras motor neuron disease, Maffucci syndrome,Majeed syndrome, Majewxki orturk syndrome, Major airway collapse, Meledadisease, Malakoplakia, Malakoplasia, Malaria, Malignant fibroushistiocytoma, Malignant germ cell tumor, Malignant hyperpyrexia,Malignant hyperthermia, Malignant mesenchymal tumor, Malignantparoxysmal ventricular tachycardia, Mallory Weiss syndrome, Maloufsyndrome, Maltase-glucoamylase deficiency, Maniac-depressive disorders,Manouvrier syndrome, Mansonellosis, Mantle cell lymphoma, Maple syrupurine disease, Marashi gorlin syndrome, Marble brain disease, Marburgdisease, Marchiafava-Micheli disease, Marcus-Gunn syndrome, Mardenwalker like syndrome, Marfan syndrome, Margarita island ectodermaldysplasia, Marin-Amat syndrome, Marinesco-Sjogren syndrome, Marionmayers syndrome, Markel-Vikkula-Mulliken syndrome, Manes greenbergpersaud syndrome, Maroteaux cohen solal bonaventure syndrome, Maroteauxle merrer bensahel syndrome, Maroteaux stanescu cousin syndrome,Maroteaux-Lamy syndrome, Maroteaux-Malamut syndrome, Marsden nyhansakati syndrome, Marshall syndrome, Marshall-Smith syndrome, Martinezmonasterio pinheiro syndrome, Martinez-Frias syndrome, Martsolfsyndrome, Massa casaer ceulemans syndrome, Mast cell leukaemia, Mastcell sarcoma, Mastocytosis, Mastroiacovo de rosa satta syndrome, Mathieude broca bony syndrome, Matsoukas liarikos giannika syndrome,Matthew-Wood syndrome, Mature B-cell tumour, Mature T-cell and NK-celltumour, May-Hegglin thrombocytopenia, Mayer-Rokitansky-Küster-Hausersyndrome, Mazabraud syndrome, McArdle disease, McCabe's disease,McCune-Albright syndrome, McDonough syndrome, McDowall syndrome, McGrathsyndrome, McKusick-Kaufman syndrome, McLeod syndrome, McPherson-Hallsyndrome, Mcalister crane syndrome, Mccallum macadam johnston syndrome,Mcgillivray syndrome, Mclain-Dekaban syndrome, Mcpherson clemenssyndrome, Meacham winn culler syndrome, Meadows' syndrome, Meckel likesyndrome, Meckel syndrome, Meckel-Gruber syndrome, Meconium aspirationsyndrome, Medeira dennis donnai syndrome, Mediastinal (thymic) largeb-cell lymphoma, Mediastinal diffuse large-cell lymphoma with sclerosis,Mediastinal fibrosis, Medrano roldan syndrome, Medullar disease,Medullary cystic kidney disease, Medulloblastoma, Megacalycosis,Megaduodenum and/or megacystis, Megaloblastic anaemia,Megarbane-Loiselet syndrome, Mehes syndrome, Mehta-Lewis-Pattonsyndrome, Meier blumberg imahorn syndrome, Meier-Gorlin syndrome, Meigedisease, Meinecke pepper syndrome, Meinecke syndrome, Melanoma, Meledadisease, Melhem fahl syndrome, Melioidosis, Melkersson rosenthalsyndrome, Melnick-Needles syndrome, Melorheostosis,Membranoproliferative glomerulonephritis, Membranous glomerulopathy,Menetrier's disease, Mengel konigsmark syndrome, Meniere's disease,Meningioma, Meningitis, Menkes syndrome, Mental retardation, Meretojasyndrome, Merkel cell carcinoma (MCC), Merlob grunebaum reisnersyndrome, Mesangial sclerosis, Mesodermic dysplasia, Mesothelioma,Mesulam syndrome, Metabolic intoxication disease, Metabolic liverdisease, Metaphyseal dysplasia, Michels syndrome, Mickleson syndrome,Micro syndrome, Microcephaly, Microcoria, Microcystic infiltratinglymphatic malformation, Microcytic anaemia, Microphthalmia, Microscopiccolitis Microtia, Microvillous inclusion disease, Mid-aortic dysplasticsyndrome, Midas syndrome, Middle aortic syndrome, Midline heart, Mietenssyndrome, Mievis verellen dumoulin syndrome, Mikati najjar sahlisyndrome, Mikulicz disease, Mild campomelic dysplasia, Miller syndrome,Miller-Dieker syndrome, Miller-Fisher syndrome (MFS), Mills syndrome,Milroy disease, Minimal change nephrotic syndrome (MCNS),Minkowski-Chauffard disease, Mirhosseini-Holmes-Walton syndrome, Mitralvalve prolapse disease, Miura syndrome, Mixed connective tissue disease,Mixed phenotype acute leukaemia, Mixed sclerosing bone dystrophy,Miyoshi myopathy, MIs syndrome, Moderate and severe traumatic braininjury, Moebius syndrome, Moerman vandenberghe fryns syndrome,Moersch-Woltman syndrome, Moeschler clarren syndrome, Mohr syndrome,Mohr-Tranebjaerg syndrome, Mollica pavone antener syndrome, Moloneysyndrome, Momo syndrome, Monilethrix, Mononen-Karnes-Senac syndrome,Monostotic fibrous dysplasia, Montefiore syndrome, Moore-Federmansyndrome, Morava-Mehes syndrome, Morgagni-Stewart-Morel syndrome,Morillo cucci passarge syndrome, Morning glory syndrome, Morquiodisease, Morris syndrome, Morse rawnsley sargent syndrome, Morvansyndrome, Moschcowitz disease, Mounier-Kuhn syndrome, Mousa-Al Din-AlNassar syndrome, Movement disease, Mowat-Wilson syndrome, Moya-moyadisease, Moynahan syndrome, Mpo deficiency, Msbd syndrome, Mseleni jointdisease (MJD), Mucha Habermann Disease, Muckle-Wells syndrome,Mucoepithelial dysplasia, Mucolipidosis, Mucopolysaccharidosis,Mucormycosis, Mucosal pemphigoid, Mucosulfatidosis, Muenke syndrome,Muir-Torre syndrome, Mullerian aplasia, Multicentric Castleman disease(MCD), Multicentric giant lymph node hyperplasia, Multicentricosteolysis, Multifocal acquired demyelinating sensory and motorneuropathy, Multifocal pattern dystrophy simulating fundusflavimaculatus, Multiglandular hyperplasia, Multiminicore disease (MmD),Multinodular goiter cystic kidney polydactyl), Multiple carboxylasedeficiency, Multiple contracture syndrome, Multiple cutaneous anduterine leiomyomas, Multiple endocrine neoplasia, Multiple epiphysealdysplasia, Multiple fibrofolliculoma, Multiple hamartoma syndrome,Multiple keratoacanthoma, Multiple pterygium syndrome, Multiplesclerosis, Multiple sulfatase deficiency, Multiple system atrophy,Multiple ventricular septal defects, Mulvihill-Smith syndrome, MURCSassociation, Murray-Puretic-Drescher syndrome, Muscular channelopathy,Muscular dystrophy, Muscular fibrosis multifocal obstructed vessels,Mutchinick syndrome, Myalgia eosinophilia associated with tryptophan,Myasthenia gravis, Myasthenic syndromes, Mycetoma, Mycoplasmaencephalitis, Mycosis fungoides, Myelinoclastic diffuse sclerosis,Myelinosis centralis diffusa, Myelocerebellar disorder, Myelodysplasticor myeloproliferative disease, Myelofibrosis with myeloid metaplasia,Myeloid sarcoma, Myeloma, Myhre syndrome, Myiasis, Myoclonic dystonia,Myoclonic epilepsy, Myodysplasia, Myofibrillar myopathy, Myoglobinuria,Myopathy and diabetes mellitus, Myopathy, Myopia, Myositis ossificansprogressiva, Myotilinopathy, Myotonia congenita, Myotonic disease,Myotubular myopathy, Myxofibrosarcoma, Myxoid liposarcoma, Myxoidmalignant fibrous histiocytoma, Myxoma with fibrous dysplasia, Möbiussyndrome, N syndrome, NACG, NAGS deficiency, NAME syndrome, NAOsyndrome, NARP syndrome, NASH syndrome, NBS, NCL, NCMD, NF 1, NFJsyndrome, NHL, NHPP, NISCH syndrome, NOMID syndrome, NPLCA, NSIP, NTD,Naegeli syndrome, Naegeli-Franceschetti-Jadassohn syndrome, Nagersyndrome, Naguib syndrome, Nail anomaly, Nail dysplasia, Naito-Oyanagidisease, Nakagawa's angioblastoma, Nakajo nishimura syndrome, Nakajosyndrome, Nakamura osame syndrome, Nance-Horan syndrome, Narcolepsywithout cataplexy, Narcolepsy-Cataplexy, Nasodigitoacoustic syndrome,Nasopharyngeal cancer, Nasu-Hakola disease, Nathalie syndrome, Navajobrainstem syndrome, Naxos disease, Necrotising hypophysitis, Necrotizingmyelitis, Nemaline myopathy, Neonatal Onset Multisystem InflammatoryDisease, Neonatal death immune deficiency, Neonatal hemochromatosis,Neonatal neutropenia, Neonatal respiratory distress syndrome,Nephroblastoma, Nephrogenic fibrosing dermopathy, Nephrogenic systemicfibrosis, Nephrolithiasis, Nephronophthisis—hepatic fibrosis,Nephropathy, Nephrosis, Nephrotic syndrome with diffuse mesangialsclerosis, Nephrotic syndrome, Nervous system tumour, Netherton disease,Neu-Laxova syndrome, Neuhauser daly magnelli syndrome, Neuhauser eichneropitz syndrome, Neuhauser's anomaly, Neural crest tumour,Neuroacanthocytosis, Neuroaxonal dystrophy, Neuroblastoma,Neurocutaneous melanosis, Neurodegeneration due to3-hydroxyisobutyryl-CoA hydrolase deficiency, Neurodegeneration withbrain iron accumulation (NBIA), Neurodegenerative disease,Neuroectodermal syndrome, Neuroepithelioma, Neurofibromatosis,Neurolipomatosis, Neuromuscular junction disease, Neuromyelitis optica,Neuromyotonia, Neuropathy, Neutral Lipid Storage Disease, Neutropaenia,Nevo syndrome, Nevoid hypermelanosis, Nezelof syndrome, Nicolaidesbaraitser syndrome, Niemann-Pick disease, Nievergelt syndrome,Niikawa-Kuroki syndrome, Nijmegen breakage syndrome,Nivelon-Nivelon-Mabille syndrome, Noack syndrome, Noble bass shermansyndrome, Nocardiosis, Nodular lymphocyte predominant Hodgkin lymphoma,Nodulosis-arthropathy-osteolysis syndrome, Noma, Non-24-Hour Sleep-Wakesyndrome, Non-DYT1 idiopathic torsion dystonia, Non-Hodgkin malignantlymphoma, Non-alcoholic steatohepatitis, Non-amyloid monoclonalimmunoglobulin deposition disease, Non-giant cell granulomatous temporalarteritis with eosinophilia, Non-infectious uveitis affecting theposterior segment of the eye, Nonaka myopathy, Nondysgerminomatous germcell tumor, Noonan like contracture myopathy hyperpyrexia, Noonan likesyndrome, Noonan syndrome, Normomorphic sialidosis, Norrie disease,Norum disease, Nova syndrome, Novak syndrome, Nuclear cell envelopathy,O donnell pappas syndrome, O'Doherty syndrome, O'Sullivan-McLeodsyndrome, OA-1, OCA, OCRL1, OFC syndrome, OFCD syndrome, OHSS, OLEDAID,ONMR syndrome, OPPG, ORW 2, OSLAM syndrome, OSMED, OTUDP syndrome,Obliterative portal venopathy, Occlusive infantile arteriopathy,Occupational allergic alveolitis, Ochoa syndrome, Ochronosis, Oculoskeletal renal syndrome, Oculo-osteo-cutaneous syndrome, Oculoectodermalsyndrome, Oculogastrointestinal muscular dystrophy, Oculomotor palsy,Oculomotor paralysis, Oculopharyngodistal myopathy, Odontologic disease,Odontomatosis, Oerter-Friedman-Anderson syndrome, Oesophageal atresia,Oguchi disease, Ohaha syndrome, Ohdo madokoro sonoda syndrome, Ohtaharasyndrome, Okamoto syndrome, Okihiro syndrome, Oligocone syndrome,Oligomeganephronia, Oliver mcfarlane syndrome, Oliver syndrome, Ollierdisease, Olmsted syndrome, Omenn syndrome, Omodysplasia, Onat syndrome,Onchocerciasis, Ondine syndrome, Ondine-Hirschsprung disease,Onychodystrophy, Oochs syndrome, Ophtalmic ichthyosis, Ophtalmoplegia,Opitz BBB/G syndrome, Opitz reynolds fitzgerald syndrome,Opitz-Caltabiano syndrome, Opitz-Frias syndrome, Oppenheim's dystonia,Opsismodysplasia, Opsoclonus-myoclonus syndrome, Optic atrophy, Opticnerve hypoplasia, Optic neuropathy, Optic pathway glioma, Orbitalleiomyoma, Ormond's disease, Ornithine aminotransferase deficiency,Orofaciodigital syndrome, Oromandibular dystonia, Oroticaciduria, Oroyafever, Osebold-Remondini syndrome, Osgood-Schlatter disease,Osler-Vaquez disease, Osteoarthropathy, Osteoblastoma, Osteochondritis,Osteochondromas, Osteochondrosis, Osteocraniostenosis, Osteodysplasia,Osteoectasia, Osteogenic sarcoma, Osteolysis, Osteomesopyknosis,Osteonecrosis, Osteopaenia, Osteopathia striata-cranial sclerosis,Osteopetrosis, Osteopoikilosis, Osteoporosis, Osteosarcoma,Osteosclerosis, Ostravik lindemann solberg syndrome, Otosclerosis,Ouvrier billson syndrome, Ovarian Sertoli-Leydig cell tumor, Ovariancancer, Ovarian germ cell malignant tumor, Ovarioleukodystrophy,Oxalosis, PAF, PAGOD syndrome, PAN, PANDAS, PAP, PAPA syndrome, PARCsyndrome, PCA, PCARP, PCH with optic atrophy, PCT, PDALS, PEHO syndrome,PEL, PELVIS syndrome, PFAPA syndrome, PFIC, PHACE syndrome, PIBIDSsyndrome, PJS, PLOSL, PMD, PNDM, POADS, POEMS syndrome, POF, POMCdeficiency, PPA, PPHS, PPM-X, PPoma, PSEK, PSP, PTC-RCC, PTLAH, PTLD,Pachygyria, Pachyonychia, Pacman dysplasia, Paediatric AutoimmuneDisorders Associated with Streptococcus infections, PaediatricAutoimmune Neuropsychiatric Disorders Associated with Streptococcusinfections, Paediatric granulomatous arthritis, Paget disease, Pagonstephan syndrome, Pai syndrome, Pallister W syndrome, Pallister-Hallsyndrome, Pallister-Killian syndrome, Palmer pagon syndrome, Palpebraldisease, Panayiotopoulos syndrome, Pancreatic carcinoma, Pancreatitis,Panner disease, Panniculitis, Panostotic fibrous dysplasia,Papillo-renal syndrome, Papillomatosis, recurrent respiratory,Papillon-Leage-Psaume syndrome, Papillon-Lefevre syndrome, Papular andsclerodermoid lichen myxedematosus, Papular atrichia, Papular mucinosisof infancy, Paramyotonia, Paraneoplastic pemphigus, Paraneoplasticretinopathy, Paraplegia, Parathyroid carcinoma, Parenchymatous liverdisease, Paris-Trousseau thrombocytopenia, Parkes-Weber syndrome,Parkinson disease, Parkinsonism-dementia-ALS complex, Paroxysmal coldhaemoglobinuria, Paroxysmal exertion-induced dyskinesia, Paroxysmalventricular fibrillation, Parry-Romberg syndrome, Parsonage-Turnersyndrome, Partial deep dermal and full thickness burns, Partingtonamyloidosis, Partington disease, Partington-Anderson syndrome,Partington-Mulley syndrome, Parvovirus antenatal infection, Pascuelcastroviejo syndrome, Pashayan syndrome, Passwell-Goodman-Siprkowskisyndrome, Patau syndrome, Patterned dystrophy of the retinal pigmentepithelium, Patterson pseudoleprechaunism syndrome, Patterson stevensonsyndrome, Patterson-Lowry rhizomelic dysplasia, Pauciarticular chronicarthritis, Pavone fiumara rizzo syndrome, Pearson syndrome, Peeling skinsyndrome, Pelget-Huer anomaly, Pelizaeus-Merzbacher brain sclerosis,Pellagra, Pemphigus, Pena-Shokeir syndrome, Pendred syndrome, Penta Xsyndrome, Pentosuria, Peptide metabolism disease, Peptidic growthfactors deficiency, Perheentupa syndrome, Periarteritis nodosa,Pericardial defect diaphragmatic hernia, Pericarditis, Perineurioma,Peripartum cardiomyopathy, Peripheral T-cell lymphoma, Peripheralneuropathy and optic atrophy, Peritoneal leiomyomatosis, Peritumoraloedema derived from brain tumours, Periventricular nodular heterotopia,Perlman syndrome, Pernicious anaemia, Perniola krajewska carnevalesyndrome, Peroxisomal beta-oxidation disease, Perrault syndrome,Persistent Mullerian duct syndrome, Peters anomaly, Peters-plussyndrome, Petges-Clejat syndrome, Petit-Fryns syndrome, Petty laxovawiedemann syndrome, Peutz-Jeghers syndrome, Peyronie syndrome, Pfeiffermayer syndrome, Pfeiffer palm teller syndrome, Pfeiffer rockeleinsyndrome, Pfeiffer syndrome, Pfeiffer-Kapferer syndrome,Pfeiffer-Singer-Zschiesche syndrome, Pfeiffer-Weber-Christian syndrome,Phacomatosis, Phaeochromocytoma, Phagocyte function anomaly, Phaversyndrome, Phelan-McDermid syndrome, Phenotypic diarrhoea,Phenylketonuria, Phocomelia, Phytosterolemia, Picardi-Lassueur-Littlesyndrome, Pick disease of brain, Piebaldism, Pierre Robin sequenceassociated with branchial archs anomalies, Pierre Robin sequenceassociated with collagen diseases, Pigeon-breeder's lung disease, Pillaysyndrome, Pilomatrixoma, Pilotto syndrome, Pinheiro freire maia mirandasyndrome, Pinsky-Di George-Harley syndrome, Pitt-Hopkins syndrome,Pitt-Williams brachydactyl), Pitt-rogers-danks syndrome, Pituitaryadenoma, Pituitary agenesis, Pituitary hormone deficiency, Pituitarylactotrophic adenoma, Pityriasis rubra pilaris, Piussan-Lenaerts-Mathieusyndrome, Plasma cell tumour, Platelet function disease, Platyspondylicdysplasia, Plectin deficiency, Pleomorphic liposarcoma, Pleuro-pulmonaryblastoma, Pleuro-pulmonary endometriosis, Plott syndrome, Plum syndrome,Plummer-Vinson syndrome, Pneumoblastoma, Pneumocystosis, Pneumoniacaused by Pseudomonas Aeruginosa, Poikilo-dermatomyositis, Pollittsyndrome, Polyarteritis nodosa, Polyarthritis, Polycystic kidneydisease, Polycystic liver disease, Polycystic ovarian disease,Polycythaemia, Polydactyl), Polyepiphyseal dysplasia, Polymicrogyria,Polymorphic catecholergic ventricular tachycardia, Polymyositis,Polyostotic fibrous dysplasia, Polyposis, Polysyndactyly-cardiacmalformation, Pompe disease, Popliteal web syndrome, Porokeratosis,Porphyria, Portal hypertension, Portal vein thrombosis, Post poliosyndrome, Post transplantation graft dysfunction, Post-poliomyeliticsyndrome, Post-transplant lymphoproliferative disease, Post-traumaticsyringomyelia, Postanginal sepsis secondary to orophyngeal infection,Posterior cortical atrophy, Postpartum cardiomyopathy, Postviral FatigueSyndrome, Potocki-Shaffer syndrome, Potter sequence, Powell chandra saalsyndrome, Powell venencie gordon syndrome, Prader-Willi syndrome, Prataliberal goncalves syndrome, Preauricular pits renal disease, PrecursorB-cell acute lymphoblastic leukaemia, Precursor T-cell acutelymphoblastic leukaemia, Preeyasombat-Varavithya syndrome,Pregnancy-related cholestasis, Premature aging, Pressure-inducedlocalized lipoatrophy, Prieto-Badia-Mulas syndrome, Prieur-Griscellisyndrome, Primary biliary cirrhosis, Primary ciliary dyskinesia, Primarycutaneous CD30-positive T-cell lymphoproliferative disorders, Primaryeffusion lymphoma, Primary effusion lymphoma associated with the humanimmunodeficiency virus (HIV) infection, Primary intestinallymphangiectasia, Primary lateral sclerosis, Primary lipodystrophy,Primary lymphoedema, Primary pulmonary lymphoma, Primary sclerosingcholangitis, Primerose syndrome, Progeria, Progressive bulbar paralysisof childhood, Progressive cone dystrophy, Progressive diaphysealdysplasia, Progressive massive osteolysis, Progressive nephropathy withhypertension, Progressive neuronal degeneration of childhood with liverdisease, Prolactinoma, Propping Zerres syndrome, Prostate cancer,Proteus syndrome, Proud-Levine-Carpenter syndrome, Prune belly syndrome,Psoriatic arthritis, PTEN Hamartoma syndrome, Pterygia, Pudendalneuralgia, Pudendal neuropathy, Pulmonar arterioveinous aneurysm,Pulmonary Langerhans' cell histiocytosis, Pulmonary alveolarmicrolithiasis, Pulmonary alveolar proteinosis, Pulmonary aorticstenosis, Pulmonary arterial hypertension, Pulmonary arterio-veinousfistula, Pulmonary artery hypoplasia, Pulmonary atresia, Pulmonaryblastoma, Pulmonary branch stenosis, Pulmonary endometriosis, Pulmonaryhaemosiderosis, Pulmonary insufficiency, Pulmonary lymphangiectasia,Pulmonary lymphangiomatosis, Pulmonary nodular lymphoid hyperplasia,Pulmonary supravalvular stenosis, Pulmonary surfactant proteinanomalies, Pulmonary valve agenesis (PVA), Pulmonary venoocclusivedisease, Pulp stones, Pulpal dysplasia, Puretic syndrome, Purtilosyndrome, Pycnodysostosis, Pyknoachondrogenesis, Pyknolepsy, Pyledisease, Pyoderma gangrenosum, Pyomyositis, Pyropoikilocytosis, Q fever,Qazi-Markouizos syndrome, Quattrin mcpherson syndrome, RAEB-1,RAPADILINO syndrome, RB-ILD, RECQ2, RECQL3, RHS, Rabson-Mendenhallsyndrome, Radiation syndromes, Radio renal syndrome, Raine syndrome,Rajab-Spranger syndrome, Rambam-Hasharon syndrome, Rambaud galiansyndrome, Ramon syndrome, Ramos arroyo clark syndrome, Ramsay huntsyndrome, Randall disease, Rapp-Hodgkin ectodermal dysplasia syndrome,Rapp-Hodgkin syndrome, Rasmussen johnsen thomsen syndrome, Rasmussensyndrome, Rathburn disease, Ray peterson scott syndrome, Raynaudphenomenon, Reardon-Baraitser syndrome, Reardon-Hall-Slaney syndrome,Recurrent hepatitis C virus induced liver disease in liver transplantrecipients, Red cell aplasia, Refetoff syndrome, Reflex sympatheticdystrophy syndrome, Refsum disease, Reginato-Schiapachasse syndrome,Reifenstein syndrome, Reinhardt pfeiffer syndrome, Reiter's syndrome,Renal adysplasia, Renal cell carcinoma, Renal dysplasia, Renalglucosuria, Renal hypertension, Renal hypoplasia, Renal nutcrackersyndrome, Renal tubular acidosis, Renal tubular disorder, Renal-colobomasyndrome, Rendu-Osler-Weber disease, Renier-Gabreels-Jasper syndrome,Renpenning syndrome, Resistance to activated protein C, Resistance tothyroid stimulating hormone, Respiratory bronchiolitis, Restless legssyndrome, Restrictive cardiomyopathy, Reticular perineurioma, Retinalarteriolar tortuosity, Retinal degeneration, Retinal dystrophy, Retinalhemorrhage, Retinoblastoma, Retinohepatoendocrinologic syndrome,Retinopathy of prematurity, Retinoschisis with early hemeralopia,Retinoschisis, Retraction syndrome, etroperitoneal fibrosis, Rett likesyndrome, Rett syndrome, Revesz-Debuse syndrome, Reye's syndrome,Reynolds syndrome, Rh deficiency syndrome, Rhabdomyosarcoma, Rheumaticfever, Rhizomelic dysplasia, Rhnull syndrome, Richards-Rundle syndrome,Richardson's syndrome, Richieri Costa-Guion Almeida-Cohen syndrome,Richieri costa da silva syndrome, Richieri costa gorlin syndrome,Richieri-Costa-Colletto syndrome, RichieriCosta-Pereira syndrome,Richner-Hanhart syndrome, Ricker syndrome, Rickettesiae disease, RiedelThyroiditis, Rieger syndrome, Right atrium familial dilatation, Rightventricle hypoplasia, Rigid spine syndrome, Riley-Day syndrome,Riley-Smith syndrome, Rippberger aase syndrome, Rippling muscle disease,Ritscher schinzel syndrome, Rivera-Perez-Salas syndrome, Robertssyndrome, Robinow syndrome, Robinow-Sorauf syndrome, Robinow-Ungersyndrome, Robinow-like syndrome, Roch-Leri mesosomatous lipomatosis,Rocky Mountain spotted fever, Rodini richieri costa syndrome, Rogerdisease, Roifman-Melamed syndrome, Rokitansky syndrome, Romano-Ward longQT syndrome, Rombo syndrome, Rommen mueller sybert syndrome,Rosai-Dorfman disease, Rosenberg lohr syndrome, Rosenberg Chutoriansyndrome, Rothmund-Thomson syndrome, Rotor syndrome, Roy maroteaux krempsyndrome, Rozin-Hertz-Goodman syndrome, Rubinstein-Taybi syndrome,Rudd-Klimek syndrome, Rudiger syndrome, Russell Silver syndrome, Russellweaver bull syndrome, Rutherfurd syndrome, Ruvalcaba syndrome,Ruvalcaba-Myhre-Smith syndrome, SADDAN, SANDO, SAPHO syndrome, SCphocomelia, SCA, SCAN 2, SCAR1, SCARF syndrome, SCASI, SCD, SCID, SCLC,SE(M)D, SGBS, SGS, SHORT syndrome, SIADH, SIBIDS syndrome, SJS, SLK,SMD, SMEI, SMMCI, SOD, SOLAMEN syndrome, SPG, SPONASTRIME dysplasia,SPS, SRP, SUNCT syndrome, Saal-Greenstein syndrome, Saccharopinuria,Sack-Barabas syndrome, Saethre-Chotzen syndrome, Saito kuba tsurutasyndrome, Sakati syndrome, Sakati-Nyhan syndrome, Sakati-Nyhan-Tisdalesyndrome, Salcedo syndrome, Salla disease, Salmonellosis, Salti salemsyndrome, Sammartino decreccio syndrome, San Luis Valley syndrome,Sandhoff disease, Sandifer syndrome, Sandrow syndrome, Sanfilippodisease, Sanjad-Sakati syndrome, Santavuori disease, Santos-Mateus-Lealsyndrome, Sarcocystosis, Sarcoidosis, Sarcosinemia, Sarcosporidiosis,Satoyoshi syndrome, Say barber hobbs syndrome, Say barber millersyndrome, Say field coldwell syndrome, Say meyer syndrome, Scarring inglaucoma filtration surgical procedures, Schaap taylor baraitsersyndrome, Scheie syndrome, Scheuermann disease, Schilbach-Rott syndrome,Schilder disease, Schimke syndrome, Schimmelpenning syndrome, Schindlerdisease, Schinzel syndrome, Schisis association, Schistosomiasis,Schmidt syndrome, Schmitt gillenwater kelly syndrome, Schneckenbeckendysplasia, Schnitzler syndrome, Schofer-Beetz-Bohl syndrome, Scholtebegeer van essen syndrome, Schopf-Schulz-Passarge syndrome,Schwannomatosis, Schwartz-Jampel syndrome, Scimitar syndrome,Scleroatrophic syndrome, Scleroderma, Scleromyxedema, Sclerosingmediastinitis, Sclerosteosis, Scott syndrome, Scott-Bryant-Grahamsyndrome, Scott-Taor syndrome, Seaver cassidy syndrome, Sebastiansyndrome, Seckel like syndrome, Seckel syndrome, Sedlackova syndrome,Seemanova lesny syndrome, Segawa syndrome, Seghers syndrome,Seitelberger disease, Selig-Benacerraf-Greene syndrome, Sellars-Beightonsyndrome, Sengers syndrome, Sengers-Hamel-Otten syndrome, Seniorsyndrome, Senior-Boichis syndrome, Senior-Loken syndrome, Sensenbrennersyndrome, Senter syndrome, Sepsis, Septic phlebitis of the internaljugular vein, Sequeiros sack syndrome, Servelle-Martorell syndrome,Setleis syndrome, Severe closed traumatic brain injury, Severe combinedimmunodeficiency T- B-, Severe combined immunodeficiency withhypereosinophilia, Severe combined immunodeficiency with leukopenia,Severe pneumococcemia, Sezary's lymphoma, Shapiro syndrome, Sharmakapoor ramji syndrome, Sharp syndrome, Sheehan syndrome, Shigellosis,Shokeir syndrome, Shone syndrome, Short QT syndrome, Short bowelsyndrome due to necrotizing enterocolitis, Short bowel syndrome due tothrombosis, Short bowel syndrome, Shprintzen omphalocele syndrome,Shprintzen-Goldberg syndrome, Shulman syndrome, Shwachman-diamondsyndrome, Shy-drager syndrome, Sialidosis, Sickle cell anaemia,Sideroblastic anaemia, Sidransky-Feinstein-Goodman syndrome, Sieglerbrewer carey syndrome, Silengo lerone pelizzo syndrome, Sillencesyndrome, Simosa penchaszadeh bustos syndrome, Simpson dysmorphiasyndrome (SDYS), Simpson-Golabi-Behmel syndrome,Sinding-Larsen-Johansson disease, Singh chhaparwal dhanda syndrome,Singh-Williams-McAlister syndrome, Single ventricular septal defect,Singleton-Merten dysplasia, Singleton-Merten syndrome, Sino-auricularheart block, Sinus node disease and myopia, Sipple syndrome,Sirenomelia, Sitosterolemia, Situs inversus viscerum-cardiopathy,Sjogren syndrome, Sjogren-Larsson syndrome, Skeletal dysplasia, Skeletalmuscle disease, Skin collagen disease, Skin vascular disease, Sleepdisorder, Sleeping seekness, Sly disease, Small bowel adenocarcinoma,Small bowel leiomyosarcoma, Small non-cleaved cell lymphoma, Smithmartin dodd syndrome, Smith-Fineman-Myers syndrome, Smith-Lemli-Opitzsyndrome, Smith-Magenis syndrome, Sneddon syndrome, Sneddon-Wilkinsondisease, Snyder-Robinson syndrome, Soft tissue perineurioma, Soft tissuesarcomas, Sohval soffer syndrome, Solitary plasmacytoma, Solomonsyndrome, Somatotroph adenoma, Sommer hines syndrome, Sommer rathbunbattles syndrome, Sommer-Young-Wee-Frye syndrome, Sondheimer syndrome,Sonoda syndrome, Sorsby syndrome, Sorsby's fundus dystrophy, Sotossyndrome, Spastic paraplegia, Spellacy gibbs watts syndrome,Spherophakia-brachymorphia, Sphingolipidosis, Spina bifida, Spinalatrophy, Spirillosis, Splenic marginal zone lymphoma,Spondylarthropathy, Spondylo camptodactyly syndrome, Spondylocostaldysostosis, Spondyloenchondrodysplasia, Spondyloepiphyseal dysplasia,Spongy degeneration of central nervous system, Spongy myocardium,Spontaneous pneumothorax familial type, Sporotrichosis, Squamous cellcarcinoma of head and neck, St Louis encephalitis, Stalker chitayatsyndrome, Stampe sorensen syndrome, Stapedo-vestibular ankylosis,Staphylococcal necrotizing pneumonia, Staphylococcal scarlet fever,Staphylococcal toxic shock syndrome, Stargardt disease, Stark-Kaesersyndrome, Startle disease, Steatocystoma, Steele-Richardson-Olszewskidisease, Stein-Leventhal syndrome, Steinert myotonic dystrophy,Steinfeld syndrome, Stern-Lubinsky-Durrie syndrome, Stevens-Johnsonsyndrome, Stickler syndrome, Stiff person syndrome, Still disease,Stimmler syndrome, Stoeling a de koomen davis syndrome, Stoll alembikfinck syndrome, Stoll geraudel chauvin syndrome, Stoll kieny dottsyndrome, Stoll-Levy-Francfort syndrome, Stomach cancer,Stormorken-Sjaastad-Langslet syndrome, Stratton garcia young syndrome,Stratton parker syndrome, Streptobacillosis, Streptococcal toxic-shocksyndrome, Stress cardiomyopathie, Strumpell-Lorrain disease,Sturge-Weber syndrome, Stuve-Wiedemann dysplasia, Subcutaneouspanniculitis-like T-cell lymphoma, Subpulmonary stenosis,Sucking/swallowing disorder, Sudden infant death syndrome, Sugarmansyndrome, Sujansky-Leonard syndrome, Sulfocysteinuria,Summerskill-Walshe-Tygstrup syndrome, Summitt syndrome, Supravalvaraortic stenosis, Susac syndrome, Sutton disease II, Sweet syndrome,Swyer syndrome, Symphalangism, Syncopal paroxysmal tachycardia, Syncopaltachyarythmia, Syndromatic diarrhea, Synovialosarcoma, Synovitis,Synspondylism, Syntelencephaly, Syringocystadenoma papilliferum,Syringomyelia, Systemic capillary leak syndrome, Systemic lupuserythematosus, Systemic mastocytosis, Systemic scleroderma (systemicsclerosis), Systemic vasculitis, T cell immunodeficiency, T-cellleukaemia, T-cell chronic lymphocytic leukaemia, TAC, TAR syndrome, TCP,TDO syndrome, TEMF, TGA, TINU syndrome, TNF receptor 1 associatedperiodic syndrome, TOS, TRAPS syndrome, TTP, TTR amyloid cardiopathy,TTR amyloid neuropathy, Tabatznik syndrome, Takatsuki syndrome, Takayasuarteritis, Takotsubo cardiomyopathy, Tang hsi ryu syndrome, Tangierdisease, Tardive dyskinesia, Tarsal Tunnel syndrome, Tarui disease,Tauopathy, Taussig-Bing syndrome, Tay syndrome, Tay-Sachs disease, Taybisyndrome, Taybi-Linder syndrome, Teebi al saleh hassoon syndrome, Teebikaurah syndrome, Teebi naguib alawadi syndrome, Teebi shaltout syndrome,Telangiectasia, Telecanthus, Telfer sugar jaeger syndrome,Temtamy-Shalash syndrome, Ter Haar syndrome, Teratoma, Tetraamelia,Tetralogy of Fallot, Thakker donnai syndrome, Thalassaemia syndrome,Thanatophoric dysplasia, Theodore's syndrome, Thiele syndrome, Thiemanndisease, Thies-Reis syndrome, Thomas jewett raines syndrome, Thomassyndrome, Thompson baraitser syndrome, Thomsen and Becker disease, Thongdouglas ferrante syndrome, Thoracic aortic aneurysm and/or dissection,Thoracic outlet syndrome, Three M disease, Thromboangiitis obliterans,Thrombocytopaenia, Thrombocytopenic purpura autoimmune, Thrombocytopenicpurpura idiopathic, Thrombocytosis, Thromboembolic pulmonaryhypertension, Thrombotic disease of haematologic origin, Thymic aplasia,Thymic carcinoma, Thyroid tumor, Tick-borne encephalitis, Tietzesyndrome, Timothy syndrome, Toliner horst manzke syndrome, Tolosa-Huntsyndrome, Tomaculous neuropathy, Tome brune fardeau syndrome,Toni-Debré-Fanconi disease, Tonoki-Ohura-Niikawa syndrome, TORCHsyndrome, Toriello syndrome, Toriello-Carey syndrome,Toriello-Higgins-Miller syndrome, Toriello-Lacassie-Droste syndrome,Torres ayber syndrome, Tourette syndrome, Townes-Brocks syndrome,Toxocariasis, Toxoplasma embryopathy, Toxoplasmosis, Tracheopathiaosteoplastica, Tranebjaerg-Svejgaard syndrome, Transmissible spongiformencephalopathies, Transposition of the great arteries with pulmonarystenosis, Transthyretin amyloid polyneuropathy, Treacher-Collinssyndrome, Aspiration pneumotitis requiring intubation and mechanicalventilation, Cardiogenic shock, Treft-Sanborn-Carey syndrome, Trenchfever, Trevor disease, Triatrial heart, Trichinosis, Tricho onychicdysplasia, Tricho-dento-osseous syndrome, Tricho-hepato-entericsyndrome, Trichorhinophalangeal, Trichorrhexis nodosa syndrome,Trichothiodystrophy, Tricuspid atresia, Triopia, Triple A syndrome,Triple H(HHH) syndrome, Triplo-X syndrome, Trisomy, Tritanopia,Trochlear dysplasia, Tropical calcific chronic pancreatitis, Tropicalendomyocardial fibrosis, Trueb burg bottani syndrome, Tsao-Ellingsonsyndrome, Tsukahara-Kajii syndrome, Tsukuhara syndrome, Tsutsugamushidisease, Tsutsugamushi fever, Tuberculosis, Tuberous sclerosis, Tubularduplication of the oesophagus, Tubular dysplasia, Tubular renaldisease-cardiomyopathy, Tubulointerstitial nephritis and uveitissyndrome, Tucker syndrome, Tuffli-Laxova syndrome, Tularaemia,Tungiasis, Tungland-Bellman syndrome, Tunnel subaortic stenosis, Turcotsyndrome, Turner syndrome, Turner-Kieser syndrome, Twin.twin transfusionsyndrome, Tylosis, ULD, UPDM, UPDP, USH, Uhl anomaly, Ulbright hodessyndrome, Ulcerative colitis, Ulerythema ophryogenesis, Ulick syndrome,Ullrich disease, Umbilical cord ulceration, Univentricular cardiopathy,Unverricht-Lundborg disease, Upington disease, Upshaw-Schulman syndrome,Urbach-Wiethe disease, Urban-Rogers-Meyer syndrome, Urban-Schosser-Spohnsyndrome, Uremic pruritus, Urrets-Zavalia syndrome, Usher syndrome,Usual interstitial pneumonia (UIP), Uveitis, VIPoma, VMCM, VODIsyndrome, VSD, VWS, Vagneur triolle ripert syndrome, Van Allen-Myhresyndrome, Van Benthem-Driessen-Hanveld syndrome, Van Bogaert disease,Van Der Woude syndrome, Van biervliet hendrickx van ertbruggen syndrome,Van de berghe-Dequeker syndrome, Van den Bosch syndrome, Van den endebrunner syndrome, Van der Knapp syndrome, Van goethem syndrome, Vanmaldergem wetzburger verloes syndrome, Van regemorter pierquin vamossyndrome, Varadi-Papp syndrome, Vascular leukoencephalopathy,Vasculitis, Vasquez-Hurst-Sotos syndrome, Vasterbotten dystrophy, Veinof Galen aneurysm, Venencie powell winkelmann syndrome, Ventricularseptal defect, Ventricular septal defect with aortic insufficiency,Verloes—Gillerot—Fryns syndrome, Verloes bourguignon syndrome, Verloesdavid syndrome, Verloes van maldergem marneffe syndrome, Verloes-Deprezsyndrome, Verloove vanhorick brubakk syndrome, Verneuil disease, Viljoenwinship syndrome, Viljoen-Kallis-Voges syndrome, Viljoen-Smart syndrome,Viral hemorrhagic fever, Viral hepatitis, Viral vasculitis, Visceralneuropathy, Vitiligo, Vitreoretinal degeneration, Vogt-Koyanagi-Haradadisease, Vohwinkel syndrome, Volcke-Soekarman syndrome, Von Gierkedisease, Von Hippel-Lindau disease, Von Recklinghausen disease, VonVoss-Cherstvoy syndrome, Von Willebrand disease, Von hippel anomaly, Vsrsyndrome, Vuopala disease, W syndrome, WAGR syndrome, WARBMI, WHIMsyndrome, WL syndrome, WT limb-blood syndrome, Waaler-Aarskog syndrome,Waardenburg syndrome, Waardenburg-Shah syndrome, Wagner disease, Waismansyndrome, Waldenström macroglobulinemia, Waldmann disease, Walker-Dysonsyndrome, Walker-Warburg syndrome, Wallis cremin beighton syndrome,Wallis zieff goldblatt syndrome, Warburg Micro syndrome, Warburg thomsensyndrome, Warburton-Anyane-Yeboa syndrome, Warman-Mulliken-Haywardsyndrome, Water-West syndrome, Waterhouse-Friedrickson syndrome, Watsonsyndrome, Weaver like syndrome, Weaver syndrome, Weaver-Williamssyndrome, Weber-Christian disease (WCD), Weber-Christian panniculitis,Webster deming syndrome, Wegener granulomatosis, Weil syndrome,Weill-Marchesani syndrome, Weismann Netter Stuhl syndrome,Weissenbacher-Zweymuller syndrome, Wellesley-Carman-French syndrome,Wells syndrome, Wells-Jankovic syndrome, Werdnig-Hoffmann disease,Wermer syndrome, Werner syndrome, Wernicke's encephalopathy,Wernicke-Korsakoff syndrome, West syndrome, West-Nile encephalitis,Westerhof-Beemer-Cormane syndrome, Western equine encephalomyelitis,Westphall disease, Whelan syndrome, Whipple disease, Whistling facesyndrome, Whooping cough, Whyte-Murphy syndrome, Wieacker-Wolffsyndrome, Wiedemann grosse dibbern syndrome, Wiedemann oldigs oppermannsyndrome, Wiedemann-Beckwith syndrome, Wiedemann-Rautenstrauch syndrome,Wildervanck syndrome, Wilkes stevenson syndrome, Wilkie-Taylor-Scamblersyndrome, Willebrand disease, Willi-Prader syndrome, Williams syndrome,Williams-Beuren syndrome, Wilms tumor, Wilson disease, Wilson-Turnersyndrome, Winchester disease, Winkelman bethge pfeiffer syndrome,Winkelmann's cytophagic panniculitis, Winship viljoen leary syndrome,Winter harding hyde syndrome, Winter-Shortland-Temple syndrome,Wiskott-Aldrich syndrome, Wissler-Fanconi syndrome, Witkop syndrome,Wittwer syndrome, Wolcott-Rallison syndrome, Wolf-Hirschhorn syndrome,Wolff zimmermann syndrome, Wolff-Parkinson-White syndrome, Wolframsyndrome, Wolman disease, Woodhouse sakati syndrome, Woods black norburysyndrome, Woods leversha rogers syndrome, Woods-Crouchman-Husonsyndrome, Worster drought syndrome, Worth syndrome, Wrinkly skinsyndrome, Wyburn-Mason syndrome, XHIGM, XLAG syndrome, XMEA, XP, Xanthicurolithiasis, Xanthinuria, Xanthogranulomatous hypophysitis,Xanthomatosis cerebrotendinous, Xerocytosis, Xeroderma pigmentosum,Yellow fever, Yellow nail syndrome, Yersiniosis, Yorifuji-Okunosyndrome, Yoshimura-takeshita syndrom, Young maders syndrome, Youngsyndrome, Young-Hugues syndrome, Young-Simpson syndrome, Yunis-Varonsyndrome, ZASP-related myofibrillar myopathy, Zadik-Barak-Levinsyndrome, Zellweger syndrome, Zellweger-like syndrome, Zimmerphocomelia, Zimmerman laband syndrome, Zinsser-Cole-Engman syndrome,Zlotogora-Ogur syndrome, Zlotogura-Martinez syndrome, Zollinger-Ellisonsyndrome, Zori stalker williams syndrome, Zunich-Kaye syndrome,Zygomycosis, 2,8 dihydroxy-adenine urolithiasis, 2-aminoadipic aciduria,2-hydroxyglutaricaciduria, 2-methylbutyric aciduria, 3 hydroxyisobutyricaciduria, 3-hydroxy-3-methylglutaric aciduria,3-methylcrotonylglycinuria, 3-methylglutaconic aciduria, 3C syndrome, 3Msyndrome, 4-hydroxybutyricaciduria, Visceral leishmaniasis, Vernalkeratoconjunctivitis, UV-A and visible light-induced photosensitivitydisorders (chronic actinic dermatitis, cutaneous porphyrias, actinicprurigo and solar urticaria), Uremic pruritus, Tricyclic antidepressantspoisoning, Traumatic spinal cord injury, Renal cell carcinoma,Superficial bladder cancer, Staphylococcus aureus bacteraemia, Spinalcord injury, Spina bifida, Soft tissue sarcoma, Small cell lung cancer,Sickle cell disease, Severe myoclonic epilepsy in infancy, Severecombined immunodeficiency (SCID), Severe closed traumatic brain injury,Retinopathy of prematurity, Retinitis pigmentosa, Respiratory distresssyndrome in premature neonates of less than 32 weeks of gestational age,Recurrent hepatitis C virus induced liver disease in liver transplantrecipients, Radiation proctitis, Pseudomonas aeruginosa lung infectionin cystic fibrosis, Progressive myoclonic epilepsies, Primary malignantbone tumors, Primary apnoea of premature newborns, Post-transplantlymphoproliferative disorders, Post-neonatal intracerebral haemorrhage,Post transplantation graft dysfunction, Polycythemia vera, Peritumoraloedema derived from brain tumors, Peripheral T-cell lymphoma (nodal,other extranodal and leukaemic/disseminated), Ductus arteriosus inpremature neonates of less than 34 weeks of gestational age, Partialdeep dermal and full thickness burns, Paroxysmal nocturnalhaemoglobinuria, Pancreatic cancer, Painful HIV-associated neuropathy,Ovarian cancer, Osteosarcoma, Orthostatic hypotension in patients withpure autonomic failure, Orthostatic hypotension in patients withmultiple system atrophy, Ornithine-transcarbamylase deficiency, Oralmucositis in head and neck cancer patients undergoing radiation therapy,Oesophageal cancer, Non-traumatic osteonecrosis, Non-ketotichyperglycinaemia, Non-infectious uveitis affecting the posterior segmentof the eye, Non-24-hour sleep-wake disorders in blind people with nolight perception, Neuroblastoma, Neovascular glaucoma, Nephriticsyndrome, Myelodysplastic syndromes, Myasthenia gravis, Moderate andsevere traumatic brain injury, Metachromatic leukodystrophy, Medullarythyroid carcinoma, Mastocytosis, Mantle cell lymphoma, Malignantmelanoma, Malignant gastrointestinal stromal tumors, Malabsorption dueto exocrine pancreatic enzyme insufficiency, Low flow priapism,Lipoprotein lipase deficiency, Ligneous conjunctivitis, Leber'shereditary optic neuropathy, Leber's congenital amaurosis, Late onsetsepsis in premature infants of less than or equal to 32 weeksgestational age, Juvenile myelomonocytic leukaemia, Japaneseencephalitis, Intestinal graft-versus-host disease, Indolentnon-Hodgkin's lymphoma, Inborn errors in primary bile acid synthesis,Hyperphenylalaninemia, Hypereosinophilic syndrome, Glioma, High-gradedysplasia in Barrett's oesophagus, Herpes simplex virus stromalkeratitis, Hereditary factor XIII deficiency, Hepatocellular carcinoma,Hepatitis B re-infection following liver transplantation, Hepaticveno-occlusive disease, Gram negative bacterial lung infection in cysticfibrosis, Gastric cancer, Gamma sarcoglycanopathy, Follicular lymphoma,Familial adenomatous polyposis, Emphysema secondary to congenitalalpha-1 antitrypsin deficiency, Duchenne muscular dystrophy, Diffuselarge B cell lymphoma, Diffuse alveolar haemorrhage, Diarrhoeaassociated with intestinal microsporidial infection, Cutaneous T-celllymphoma, Cutaneous forms of lupus erythematosus, Cushing's syndromesecondary to ectopic ACTH secretion, Corneal graft rejection, Congenitalvenous malformations, Congenital lymphatic malformations, Congenitalalpha-1 antitrypsin deficiency, Congenital adrenal hyperplasia, Chronicpain, Cocaine poisoning, Chronic myeloid leukaemia, Chronic lymphocyticleukaemia, Chronic iron overload requiring chelation therapy, Chronicidiopathic myelofibrosis, Chronic eosinophilic leukaemia and thehypereosinophilic syndrome, Cholangiocarcinoma, Charcot-Marie-Toothdisease type 1A, Cardiogenic shock, Bronchopulmonary dysplasia inpremature neonates of less than 30 weeks of gestational age, B-cellchronic lymphocytic leukemia, Autoimmune uveitis, Atypical HaemolyticUraemic Syndrome (aHUS) associated with an inherited abnormality of thecomplement system, Aspiration pneumonitis requiring intubation andmechanical ventilation, Aneurysmal subarachnoid haemorrhage, Anaplasticthyroid cancer, Anal fistula, Acute sensorineural hearing loss (acuteacoustic trauma, sudden deafness and surgery induced acoustic trauma),Acute peripheral arterial occlusion, Acute intermittent porphyria,Active phase of Peyronie's disease, Acanthamoeba keratitis,A-mannosidosis, 5q spinal muscular atrophy, Cavopulmonary Anastomosis,Atrial Septal Defects (ASD), Partial Anomalous Pulmonary Venous Return,Persistent Common Atrio Ventricular Canal Endocardial Cushion Defect.Ostium Primum, Single Atrium, Patent Ductus Arteriosus (PDA), TotalAnomalous Pulmonary Venous Return, Ventricular Septal Defects (VSD),Pulmonary Valve Stenosis, Pulmonary Artery Stenosis and Stenosis ofPulmonary Artery Branches, Pulmonary Atresia with Intact VentricularSeptum, Congenital Mitral Valve Disease, Aortic Valvular Stenosis andCongenital Aortic Valvular Regurgitation, Supravalvular Aortic Stenosis,Transposition of the Great Arteries, Double Outlet Right Ventricle,Corrected Transposition of the Great Arteries, Truncus Arteriosus, AortoPulmonary Window, Tricuspid Atresia, Ebstein Anomaly, Malformations ofthe Vena Cava, Coarctation of the Aorta, Atresia of Aortic Valve,Anomalies of the Aortic Arch, Anomalous Origin of the Right SubclavianArtery with Coarctation of the Aorta, Idiopathic Dilatation of thePulmonary Artery, Left Pulmonary Artery Arising from Right PulmonaryArtery, Dextrocardia—Situs Inversus Totalis, Association of HeartMalformations with Asplenia, Malformations of the Vena Cava, CongenitalCoronary Artery Arterio-Venous Fistula, Abnormal Origin of the CoronaryArteries, Aneurysm of the Sinus of Valsalva (Aortic Sinus Aneurysm),Endocardial Fibroelastosis, Idiopathic Hypertrophic Subaortic Stenosis(1HSS), Mitral Valve Prolapse—Barlow's Syndrome, Hypoplastic Left Heart.

Pharmaceutical Compositions

Still another aspect of the present invention relates to the use of thepeptide of the invention and the inventive peptide combination as anactive ingredient, together with at least one pharmaceuticallyacceptable carrier, excipient and/or diluents for the manufacture of apharmaceutical composition for the treatment and/or prophylaxis ofcancer, an autoimmune disease, a fibrotic disease, an inflammatorydisease, a neurodegenerative disease, an infectious disease, a lungdisease, a heart and vascular disease or a metabolic disease or anyother disease disclosed herein.

Such pharmaceutical compositions comprise the peptide or the peptidecombination as an active ingredient, together with at least onepharmaceutically acceptable carrier, excipient, binders, disintegrates,glidents, diluents, lubricants, coloring agents, sweetening agents,flavoring agents, preservatives or the like. The pharmaceuticalcompositions of the present invention can be prepared in a conventionalsolid or liquid carrier or diluents and a conventionalpharmaceutically-made adjuvant at suitable dosage level in a known way.Preferably, the two peptides are contained in the combination in anamount from 20% by weight of peptide 1 to 80% by weight of peptide 2 to80% by weight of peptide 1 to 20% by weight of peptide 2. Morepreferably, the two peptides are contained in the combination in anamount from 30% by weight of peptide 1 to 70% by weight of peptide 2 to70% by weight of peptide 1 to 30% by weight of peptide 2. Still morepreferably the two peptides are contained in the combination in anamount from 40% by weight of peptide 1 to 60% by weight of peptide 2 to60% by weight of peptide 1 to 40% by weight of peptide 2.

Preferably the peptide or the peptide combination is suitable forintravenous administration or suitable for oral administration orsuitable for administration by inhalation.

Administration forms include, for example, pills, tablets, film tablets,coated tablets, capsules, liposomal formulations, micro- andnano-formulations, powders and deposits. Furthermore, the presentinvention also includes pharmaceutical preparations for parenteralapplication, including dermal, intradermal, intragastral, intracutan,intravasal, intravenous, intramuscular, intraperitoneal, intranasal,intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual,topical, or transdermal application, which preparations in addition totypical vehicles and/or diluents contain the peptide or the peptidecombination according to the present invention.

The present invention also includes mammalian milk, artificial mammalianmilk as well as mammalian milk substitutes as a formulation for oraladministration of the peptide combination to newborns, toddlers, andinfants, either as pharmaceutical preparations, and/or as dietary foodsupplements.

The peptide or the peptide combination of the invention can also beadministered in form of its pharmaceutically active salts. Suitablepharmaceutically active salts comprise acid addition salts and alkali orearth alkali salts. For instance, sodium, potassium, lithium, magnesiumor calcium salts can be obtained.

The peptide or the peptide combination of the invention formspharmaceutically acceptable salts with organic and inorganic acids.Examples of suitable acids for such acid addition salt formation arehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid,p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbicacid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid,nitric acid, formic acid, propionic acid, gluconic acid, lactic acid,tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid,benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid,methanesulfonic acid, ethanesulfonic acid, nitrous acid,hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonicacid, naphthylsulfonic acid, sulfanilic acid, camphersulfonic acid,china acid, mandelic acid, o-methylmandelic acid,hydrogen-benzenesulfonic acid, picric acid, adipic acid,D-o-tolyltartaric acid, tartronic acid, α-toluic acid, (o, m, p)-toluicacid, naphthylamine sulfonic acid, and other mineral or carboxylic acidswell known to those skilled in the art. The salts are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce a salt in the conventional manner.

The pharmaceutical compositions according to the present invention willtypically be administered together with suitable carrier materialsselected with respect to the intended form of administration, i.e. fororal administration in the form of tablets, capsules (either solidfilled, semi-solid filled or liquid filled), powders for constitution,aerosol preparations consistent with conventional pharmaceuticalpractices. Other suitable formulations are gels, elixirs, dispersiblegranules, syrups, suspensions, creams, lotions, solutions, emulsions,suspensions, dispersions, and the like. Suitable dosage forms forsustained release include tablets having layers of varyingdisintegration rates or controlled release polymeric matricesimpregnated with the active components and shaped in tablet form orcapsules containing such impregnated or encapsulated porous polymericmatrices. The pharmaceutical compositions may be comprised of 5 to 95%by weight of the peptide or the peptide combination, while also up to100% of the pharmaceutical composition can consist of the peptidecombination.

As pharmaceutically acceptable carrier, excipient and/or diluents can beused lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filledcapsules).

Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethyl-cellulose, polyethylene glycol and waxes. Among thelubricants that may be mentioned for use in these dosage forms, boricacid, sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrants include starch, methylcellulose, guar gum and the like.Sweetening and flavoring agents and preservatives may also be includedwhere appropriate. Some of the terms noted above, namely disintegrants,diluents, lubricants, binders and the like, are discussed in more detailbelow.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects. Suitable dosage forms for sustainedrelease include layered tablets containing layers of varyingdisintegration rates or controlled release polymeric matricesimpregnated with the active components and shaped in tablet form orcapsules containing such impregnated or encapsulated porous polymericmatrices.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The peptide or the peptide combination of the present invention may alsobe deliverable transdermally. The transdermal compositions may take theform of creams, lotions, aerosols and/or emulsions and can be includedin a transdermal patch of the matrix or reservoir type as areconventional in the art for this purpose.

The transdermal formulation of the peptide or the peptide combination ofthe invention is understood to increase the bioavailability of saidpeptide into the circulating blood. One problem in the administration ofpeptide(s) is the loss of bioactivity due to the formation of insolublesin aqueous environments or due to degradation. Therefore stabilizationof peptide(s) for maintaining their fluidity and maintaining theirbiological activity upon administration to the patients in need thereofneeds to be achieved.

Prior efforts to provide active agents for medication includeincorporating the medication in a polymeric matrix whereby the activeingredient is released into the systemic circulation. Knownsustained-release delivery means of active agents are disclosed, forexample, in U.S. Pat. No. 4,235,988, U.S. Pat. No. 4,188,373, U.S. Pat.No. 4,100,271, US447-471, U.S. Pat. No. 4,474,752, U.S. Pat. No.4,474,753, or U.S. Pat. No. 4,478,822 relating to polymericpharmaceutical vehicles for delivery of pharmaceutically active chemicalmaterials to mucous membranes. The pharmaceutical carriers are aqueoussolutions of certain polyoxyethylene-polyoxypropylene condensates. Thesepolymeric pharmaceutical vehicles are described as providing forincreased drug absorbtion by the mucous membrane and prolonged drugaction by a factor of two or more. The substituents are block copolymersof polyoxypropylene and polyoxyethylene used for stabilization of drugssuch as insulin.

Aqueous solutions of polyoxyethylene-polyoxypropylene block copolymers(poloxamers) are useful as stabilizers for peptide(s). Aside fromserving as a stabilizer for the peptide(s), poloxamers provide excellentvehicles for the delivery of the peptide(s), and they arephysiologically acceptable. Poloxamers, also known by the trade namePluronics (e.g. Pluronic F127, Pluronic P85, Pluronic F68) havesurfactant properties that make them useful in industrial applications.Among other things, they can be used to increase the water solubility ofhydrophobic, oily substances or otherwise increase the miscibility oftwo substances with different hydrophobicities. For this reason, thesepolymers are commonly used in industrial applications, cosmetics, andpharmaceuticals. They have also been used as model systems for drugdelivery applications. In situ gelation of pharmaceutical compositionsbased on poloxamer that are biologically triggered are known in the art(e.g. U.S. Pat. No. 5,256,396), describing compositions containingpoloxamer 407 and water at specified concentrations.

The term capsule refers to a special container or enclosure made ofmethyl cellulose, polyvinyl alcohols, or denatured gelatins or starchfor holding or containing compositions comprising the activeingredients. Hard shell capsules are typically made of blends ofrelatively high gel strength bone and pork skin gelatins. The capsuleitself may contain small amounts of dyes, opaquing agents, plasticizersand preservatives.

Tablet means compressed or molded solid dosage form containing theactive ingredients with suitable diluents. The tablet can be prepared bycompression of mixtures or granulations obtained by wet granulation, drygranulation or by compaction well known to a person skilled in the art.

Oral gels refers to the active ingredients dispersed or solubilized in ahydrophilic semi-solid matrix.

Powders for constitution refer to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices. One example for such an oral administration form for newborns,toddlers and/or infants is a human breast milk substitute which isproduced from milk powder and milk whey powder, optionally and partiallysubstituted with lactose.

Human breast milk is a complex fluid, rich in nutrients and innon-nutritional bioactive components. It contains all of the nutrientsneeded by the newborn baby. These include the metabolic components (fat,protein, and carbohydrates), water, and the raw materials for tissuegrowth and development, such as fatty acids, amino acids, minerals,vitamins, and trace elements.

More than 98% of the fat in is in the form of triglycerides. Oleic acidand palmitic acid are the most abundant fatty acids in breastmilktriglycerides, with comparatively high proportions of the essentialfatty acids, and linolenic acid, followed by long-chain polyunsaturatedfatty acids, such as arachidonic acid and docosahexaenoic acid. Theselong-chain fatty acids are constituents of brain and neural tissue andare needed in early life for mental and visual development. The lipidcomponent of breast milk is the transport vehicle for fat-solublemicronutrients such as prostaglandins and vitamins A, D, E, and K.

Proteins account for approximately 75% of the nitrogen-containingcompounds in breast milk. Non-protein nitrogen substances include urea,nucleotides, peptides, free amino acids, and DNA. The proteins of breastmilk can be divided into two categories: micellar caseins and aqueouswhey proteins, present in the ratio of about 40:60. Casein formsmicelles of relatively small volume and produces a soft, flocculent curdin the infant's stomach. The major whey proteins are lactalbumin,lactoferrin, secretory IgA, and serum albumin, with a large number ofother proteins and peptides present in smaller amounts.

The principal carbohydrate is lactose, a disaccharide produced in themammary epithelial cell from glucose by a reaction involvinglactalbumin.

In addition to the nutritional components, breast milk contains a wealthof bioactive components that have beneficial non-nutritional functions.These include a wide range of specific and non-specific antimicrobialfactors; cytokines and anti-inflammatory substances; and hormones,growth modulators, and digestive enzymes (Table 1), many of which havemultiple activities. These components may be of particular importancefor young infants because of the immaturity of the host defense anddigestive systems early in life.

TABLE 1 Examples of the non-nutritional components of breast milkAntimicrobial factors secretory IgA, IgM, IgG lactoferrin lysozymecomplement C3 leucocytes bifidus factor lipids and fatty acids antiviralmucins, GAGs oligosaccharides Cytokines and anti-inflammatory factorstumor necrosis factor interleukins interferons prostaglandinsantichymotrypsin antitrypsin platelet-activating factor Hormonesfeedback inhibitor of lactation (FIL) insulin prolactin thyroid hormonescorticosteroids ACTH oxytocin calcitonin parathyroid hormoneerythropoietin Growth factors epidermal (EGF) nerve (NGF) insulin-like(IGF) transforming (TGF) taurine polyamines Digestive enzymes amylasebile acid-stimulating esterase bile acid-stimulating lipases lipoproteinlipase Transporters lactoferrin (Fe) folate binder cobalamin binder IgFbinder thyroxine binder corticosteroid binder

Besides breast milk, infant formula is the only other infant milk whichthe medical community considers nutritionally acceptable for infantsunder the age of one year. Cow's milk is not recommended because of itshigh protein and electrolyte (salt) content which may harm infant'simmature kidneys. The nutrient content of infant formula shouldcomprise: Protein, Fat, Linoleic acid, Vitamins: A, C, D, E, K, thiamin(B1), riboflavin (B2), B6, B12, Niacin, Folic acid, Pantothenic acid,Calcium, Metals: magnesium, iron, zinc, manganese, copper; Phosphorus,Iodine, Sodium chloride, Potassium chloride. In addition, formulas notmade with cow's milk must include biotin, choline, and inositol.Hypoallergenic formulas reduce the likelihood of certain medicalcomplications in babies with specific health problems. Baby formula canbe synthesized from raw amino acids. This kind of formula is sometimesreferred to as elemental infant formula or as medical food because ofits specialized nature. Powder blends containing the active ingredientsand suitable diluents which can be suspended in water or juices can beproduced by spray drying.

Spray drying has been found the most suitable process for removing thelast part of the water, since spray drying can convert milk concentrateinto a powder while still keeping the valuable properties of the milk.The principle of all spray dryers is to transform the concentrate intomany small droplets which are then exposed to a fast current of hot air.Because of the very large surface area of the droplets, the waterevaporates almost instantaneously and the droplets are transformed intopowder particles.

Powdered milk is a powder made from dried milk solids. Powdered milk hasa far longer shelf life than liquid milk and does not need to berefrigerated due to its low moisture content.

Instant milk powder is produced by partially rehydrating the dried milkpowder particles causing them to become sticky and agglomerate. Thewater is then removed by drying resulting in an increased amount of airincorporated between the powder particles.

Milk powder manufacture is a process carried out on a large scale. Itinvolves the gentle removal of water, while retaining all the desirablenatural properties of the milk like colour, flavour, solubility,nutritional value.

Milk powder process includes spray drying, fluid bed processing,extraction, evaporation and freeze drying. Other processes are freezeconcentration, filteration, and homogenisation.

The artificial mother milk formulations or mother milk substitutes ofthe present invention are preferably prepared by adding to a mother milkformulation including commercially available mother milk formulationsespecially in powder form the peptide or inventive peptide combination.The peptide or peptide combination is preferably added in an amount of3-100 μg peptide or peptide combination per 100 ml (commerciallyavailable) mother milk formulation, more preferably in an amount of 5-70μg/100 ml and most preferably in an amount of 10-40 μg/100 ml mothermilk formulation.

Suitable diluents are substances that usually make up the major portionof the composition or dosage form. Suitable diluents include sugars suchas lactose, sucrose, mannitol and sorbitol, starches derived from wheat,corn rice and potato, and celluloses such as microcrystalline cellulose.The amount of diluents in the composition can range from about 5 toabout 95% by weight of the total composition, preferably from about 25to about 75%, more preferably from about 30 to about 60% by weight, andmost preferably from about 40 to 50% by weight.

The term disintegrants refers to materials added to the composition tohelp it break apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches, “cold water soluble” modified starchessuch as sodium carboxymethyl starch, natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar, cellulose derivativessuch as methylcellulose and sodium carboxymethylcellulose,microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose, alginates such as alginic acid and sodiumalginate, clays such as bentonites, and effervescent mixtures. Theamount of disintegrant in the composition can range from about 1 toabout 40% by weight of the composition, preferably 2 to about 30% byweight of the composition, more preferably from about 3 to 20% by weightof the composition, and most preferably from about 5 to about 10% byweight.

Binders characterize substances that bind or “glue” powders together andmake them cohesive by forming granules, thus serving as the “adhesive”in the formulation. Binders add cohesive strength already available inthe diluents or bulking agent.

Suitable binders include sugars such as sucrose, starches derived fromwheat, corn rice and potato; natural gums such as acacia, gelatin andtragacanth; derivatives of seaweed such as alginic acid, sodium alginateand ammonium calcium alginate; cellulosic materials such asmethylcellulose and sodium carboxymethylcellulose andhydroxypropyl-methylcellulose; polyvinylpyrrolidone; and inorganics suchas magnesium aluminum silicate. The amount of binder in the compositioncan range from about 1 to 30% by weight of the composition, preferablyfrom about 2 to about 20% by weight of the composition, more preferablyfrom about 3 to about 10% by weight, even more preferably from about 3to about 6% by weight.

Lubricant refers to a substance added to the dosage form to enable thetablet, granules, etc. after it has been compressed, to release from themold or die by reducing friction or wear. Suitable lubricants includemetallic stearates such as magnesium stearate, calcium stearate orpotassium stearate; stearic acid; high melting point waxes; and watersoluble lubricants such as sodium chloride, sodium benzoate, sodiumacetate, sodium oleate, polyethylene glycols and d'Ideucine. Lubricantsare usually added at the very last step before compression, since theymust be present on the surfaces of the granules and in between them andthe parts of the tablet press. The amount of lubricant in thecomposition can range from about 0.05 to about 15% by weight of thecomposition, preferably 0.2 to about 5% by weight of the composition,more preferably from about 0.3 to about 3%, and most preferably fromabout 0.3 to about 1.5% by weight of the composition.

Glidents are materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.01 to 10% by weight ofthe composition, preferably 0.1% to about 7% by weight of the totalcomposition, more preferably from about 0.2 to 5% by weight, and mostpreferably from about 0.5 to about 2% by weight.

Coloring agents are excipients that provide coloration to thecomposition or the dosage form. Such excipients can include food gradedyes and food grade dyes adsorbed onto a suitable adsorbent such as clayor aluminum oxide. The amount of the coloring agent can vary from about0.01 to 10% by weight of the composition, preferably from about 0.05 to6% by weight, more preferably from about 0.1 to about 4% by weight ofthe composition, and most preferably from about 0.1 to about 1%.

Peptide(s) of the invention can be used to form multiparticulates,discrete particles, well known dosage forms, whose totality representsthe intended therapeutically useful dose of a drug. When taken orally,multiparticulates generally disperse freely in the gastrointestinaltract, and maximize absorption. A specific example is described in U.S.Pat. No. 6,068,859, disclosing multiparticulates that provide controlledrelease of azithromycin. Another advantage of the multiparticulates isthe improved stability of the drug. The poloxamer component of themultiparticulate is very inert, thus minimizing degradation of the drug.

However, formulation problems result from the melt-congeal process oftenused to form multiparticulates. The multiparticulates are preferablyformed into round beads or spheres. Some carriers, when melted and thensolidified, do not form round beads but may solidify into rods, strings,or other non-spherical shapes. The result is very irregularly shapedmultiparticulates that are difficult to process into dosage forms. Thisproblem is solved by e.g. WO 2007104173 where the particles consist of apoloxamer, a resin, and/or a tocopherol, creating together with themedicament (e.g. insulin) micelles. Micelle formation is essential forthe absorption of many nutrients within the human body. Bile saltsformed in the liver and secreted by the gall bladder allow micelles offatty acids to form. This allows the absorption of complicated lipidsand lipid soluble vitamins within the micelle by the small intestine.Micelles are approximately spherical in shape. Preferably, the peptideor the peptide combination of the invention are formulated with apoloxamer and a resin to form micelles suitable for oral administrationto patients in need of the medicament.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injections or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Other preferred pharmaceutical compositions are buffered solutions. Theterm buffer, buffer system, buffer solution and buffered solution, whenused with reference to hydrogen-ion concentration or pH, refers to theability of a system, particularly an aqueous solution, to resist achange of pH on adding acid or alkali, or on dilution with a solvent.Preferred buffer systems can be selected from the group consisting offormate (pKa=3.75), lactate (pKa=3.86), benzoic acid (pKa=4.2) oxalate(pKa=4.29), fumarate (pKa=4.38), aniline (pKa=4.63), acetate buffer(pKa=4.76), citrate buffer (pKa2=4.76, pKa3=6.4), glutamate buffer(pKa=4.3), phosphate buffer (pKa=7.20), succinate (pKa1=4.93;pKa2=5.62), pyridine (pKa=5.23), phthalate (pKa=5.41); histidine(pKa=6.04), MES (2-(N-morpholino)ethanesulphonic acid; pKa=6.15); maleicacid (pKa=6.26); cacodylate (dimethylarsinate, pKa=6.27), carbonic acid(pKa=6.35), ADA (N-(2-acetamido)imino-diacetic acid (pKa=6.62); PIPES(4-piperazinebis-(ethanesulfonic acid; BIS-TRIS-propane(1,3-bis[tris(hydroxymethyl)methylamino]-propane), pKa=6.80),ethylendiamine (pKa=6.85), ACES2-[(2-amino-2-oxoethyl)amino]ethanesulphonic acid; pKa=6.9), imidazole(pKa=6.95), MOPS (3-(N-morphin)-propansulfonic acid; pKa=7.20),diethylmalonic acid (pKa=7.2), TES (2-[tris(hydroxymethyl) methyl]aminoethanesulphonic acid; pKa=7.50) and HEPES(N-2-hydroxylethylpiperazin-N″-2-ethansulfonic acid; pKa=7.55) buffersor other buffers having a pKa between 3.8 to 7.7.

Preferred is the group of carboxylic acid buffers such as acetate andcarboxylic diacid buffers such as fumarate, tartrate and phthalate andcarboxylic triacid buffers such as citrate. Another group of preferredbuffers is represented by inorganic buffers such as sulfate, borate,carbonate, oxalate, calcium hydroxyde and phosphate buffers. Anothergroup of preferred buffers are nitrogen containing buffers such asimidazole, diethylenediamine, and piperazine.

Also preferred are sulfonic acid buffers such as TES, HEPES, ACES,PIPES, [(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]-1-propanesulfonicacid (TAPS), 4-(2-hydroxyethyl)piperazine-1-propanesulfonic acid (EPPS),4-Morpholinepropanesulfonic acid (MOPS) andN,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES).

Another group of preferred buffers are glycine buffers such as glycine,glycyl-glycine, glycyl-glycyl-glycine, N,N-bis(2-hydroxyethyl)glycineand N-[2-hydroxy-1,1-bis(hydroxy-methyl)ethyl]glycine (Tricine).

Preferred are also amino acid buffers such as glycine, alanine, valine,leucine, isoleucine, serine, threonine, phenylalanine, tyrosine,tryptophane, lysine, arginine, histidine, aspartate, glutamate,asparagine, glutamine, cysteine, methionine, proline, 4-hydroxyproline,N,N,N-trimethyllysine, 3-methylhistidine, 5-hydroxylysine,O-phosphoserine, γ-carboxyglutamate, ε-N-acetyllysine,ω-N-methylarginine, citrulline, ornithine and derivatives thereof.

TABLE 2 Also preferred are the following buffers: effective pH range pKa25° C. buffer 2.7-4.2 3.40 malate (pK1) 3.0-4.5 3.75 formate 3.0-6.24.76 citrate (pK2) 3.2-5.2 4.21 succinate (pK1) 3.6-5.6 4.76 acetate3.8-5.6 4.87 propionate 4.0-6.0 5.13 malate (pK2) 4.9-5.9 5.23 pyridine5.0-6.0 5.33 piperazine (pK1) 5.0-7.4 6.27 cacodylate 5.5-6.5 5.64succinate (pK2) 5.5-6.7 6.10 MES 5.5-7.2 6.40 citrate (pK3) 5.5-7.2 6.24maleate (pK2) 5.5-7.4 1.70, 6.04, 9.09 histidine 5.8-7.2 6.46 bis-tris5.8-8.0 7.20 phosphate (pK2)  6.0-12.0 9.50 ethanolamine 6.0-7.2 6.59ADA 6.0-8.0 6.35 carbonate (pK1) 6.1-7.5 6.78 ACES 6.1-7.5 6.76 PIPES6.2-7.6 6.87 MOPSO 6.2-7.8 6.95 imidazole 6.3-9.5 6.80, 9.00 BIS-TRISpropane 6.4-7.8 7.09 BES 6.5-7.9 7.14 MOPS 6.8-8.2 7.48 HEPES 6.8-8.27.40 TES 6.9-8.3 7.60 MOBS 7.0-8.2 7.52 DIPSO 7.0-8.2 7.61 TAPSO 7.0-8.37.76 triethanolamine (TEA) 7.0-9.0 0.91, 2.10, 6.70, 9.32 pyrophosphate7.1-8.5 7.85 HEPPSO 7.2-8.5 7.78 POPSO

Preferred are the buffers having an effective pH range of from 2.7 to8.5, and more preferred of from 3.8 to 7.7. The effective pH range foreach buffer can be defined as pKa−1 to pKa+1, where Ka is the ionizationconstant for the weak acid in the buffer and pKa=−log K.

Most preferred are buffers suitable for pharmaceutical use e.g. bufferssuitable for administration to a patient such as acetate, carbonate,citrate, fumarate, glutamate, lactate, phosphate, phthalate, andsuccinate buffers. Particularly preferred examples of commonly usedpharmaceutical buffers are acetate buffer, citrate buffer, glutamatebuffer and phosphate buffer. Also most preferred is the group ofcarboxylic acid buffers. The term “carboxylic acid buffers” as usedherein shall refer to carboxylic mono acid buffers and carboxylic diacidbuffers as well as carboxylic triacid buffers. Of course alsocombinations of buffers, especially of the buffers mentioned herein areuseful for the present invention.

Some suitable pharmaceutical buffers are a citrate buffer (preferably ata final formulation concentration of from about 20 to 200 mM, morepreferably at a final concentration of from about 30 to 120 mM) or anacetate buffer (preferably at a final formulation concentration of about20 to 200 mM) or a phosphate buffer (preferably at a final formulationconcentration of about 20 to 200 mM).

Techniques for the formulation and administration of the peptide or thepeptide combination of the present invention may be found in“Remington's Pharmaceutical Sciences” Mack Publishing Co., Easton Pa. Asuitable composition comprising at least one peptide mentioned hereinmay be a solution of the peptide or the peptide combination in asuitable liquid pharmaceutical carrier or any other formulation such astablets, pills, film tablets, coated tablets, dragees, capsules, powdersand deposits, gels, syrups, slurries, suspensions, emulsions, and thelike.

A particularly preferred pharmaceutical composition is a lyophilised(freeze-dried) preparation (Iyophilisate) suitable for administration byinhalation or for intravenous administration. To prepare the preferredlyophilised preparation the peptide or the peptide combination of theinvention are solubilised in a 4 to 5% (w/v) mannitol solution and thesolution is then lyophilised. The mannitol solution can also be preparedin a suitable buffer solution as described above.

Further examples of suitable cryo-/lyoprotectants (otherwise referred toas bulking agents or stabilizers) include thiol-free albumin,immunoglobulins, polyalkyleneoxides (e.g. PEG, polypropylene glycols),trehalose, glucose, sucrose, sorbitol, dextran, maltose, raffinose,stachyose and other saccharides (cf. for instance WO 97/29782), whilemannitol is used preferably. These can be used in conventional amountsin conventional lyophilization techniques. Methods of lyophilisation arewell known in the art of preparing pharmaceutical formulations.

For administration by inhalation the particle diameter of thelyophilised preparation is preferably between 2 to 5 μm, more preferablybetween 3 to 4 μm. The lyophilised preparation is particularly suitablefor administration using an inhalator, for example the OPTINEB® orVENTA-NEB® inhalator (NEBU-TEC, Elsenfeld, Germany). The lyophilisedproduct can be rehydrated in sterile distilled water or any othersuitable liquid for inhalation administration.

Alternatively for intravenous administration the lyophilised product canbe rehydrated in sterile distilled water or any other suitable liquidfor intravenous administration.

After rehydration for administration in sterile distilled water oranother suitable liquid the lyophilised preparation should have theapproximate physiological osmolality of the target tissue for therehydrated peptide preparation i.e. blood for intravenous administrationor lung tissue for inhalation administration. Thus it is preferred thatthe rehydrated formulation is substantially isotonic.

The preferred dosage concentration for either intravenous, oral, orinhalation administration is between 100 to 2000 μmole/ml, and morepreferably is between 200 to 800 pmole/ml. These are also the preferredranges of the peptide combination in the mother milk substitute orartificial mother milk formulation or the pharmaceutical compositionsdisclosed herein.

Dietary Supplement

Still another aspect of the present invention relates to the use ofdisclosed peptide and peptide combination as a dietary supplement. Thatdietary supplement is preferably for oral administration and especiallybut not limited to administration to newborns, toddlers, and/or infants.A dietary supplement is intended to supplement the diet. The “dietaryingredients” in these products may in addition include: vitamins,minerals, herbs or other botanicals, amino acids, and substances such asenzymes, organ tissues, glandulars, and metabolites. Dietary supplementsmay be manufactured in forms such as tablets, capsules, softgels,gelcaps, liquids, or powders.

Method of Treatment

Another aspect of the present invention relates to a method ofprophylaxis and/or treatment of cancer, an autoimmune disease, afibrotic disease, an inflammatory disease, a neurodegenerative disease,an infectious disease, a lung disease, a heart and vascular disease or ametabolic disease or any other disease disclosed herein comprisingadministering to a patient in need thereof a pharmaceutical compositioncomprising the peptide or the peptide combination according to thepresent invention in a therapeutically effective amount effective totreat the afore-mentioned disease.

Accordingly, the terms “prophylaxis” or “treatment” includes theadministration of the peptide or the peptide combination of the presentinvention to prevent, inhibit, or arrest the symptoms of an infectiousdisease, an autoimmune disease, a fibrotic disease, an inflammatorydisease, a neurodegenerative disease, or a heart and vascular disease.In some instances, treatment with the peptide or the peptide combinationof the present invention will be done in combination with otherprotective compounds to prevent, inhibit, or arrest the symptoms of aninfectious disease, an autoimmune disease, a fibrotic disease, aninflammatory disease, a neurodegenerative disease, or a heart andvascular disease.

The term “active agent” or “therapeutic agent” as used herein refers toan agent that can prevent, inhibit, or arrest the symptoms and/orprogression of an infectious, an autoimmune disease, a fibrotic disease,an inflammatory disease, a neurodegenerative disease, a heart andvascular disease or any other disease disclosed herein.

The term “therapeutic effect” as used herein, refers to the effectiveprovision of protection effects to prevent, inhibit, or arrest thesymptoms and/or progression of an infectious, an autoimmune disease, afibrotic disease, an inflammatory disease, a neurodegenerative disease,or a heart and vascular disease.

The term “a therapeutically effective amount” as used herein means asufficient amount of the peptide or the peptide combination of theinvention to produce a therapeutic effect, as defined above, in asubject or patient in need of treatment.

The terms “subject” or “patient” are used herein mean any mammal,including but not limited to human beings, including a human patient orsubject to which the compositions of the invention can be administered.The term mammals include human patients and non-human primates, as wellas experimental animals such as rabbits, rats, and mice, and otheranimals.

The peptide or the peptide combination of the present invention can beused for the prophylaxis and/or treatment of cancer, an autoimmunedisease, a fibrotic disease, an inflammatory disease, aneurodegenerative disease, an infectious disease, a lung disease, aheart and vascular disease or a metabolic disease or any other diseasementioned herein in combination administration with another therapeuticcompound. As used herein the term “combination administration” of acompound, therapeutic agent or known drug with the peptide or thepeptide combination of the present invention means administration of thedrug and the peptide or the peptide combination at such time that boththe known drug and the peptide or the peptide combination will have atherapeutic effect. In some cases this therapeutic effect will besynergistic. Such concomitant administration can involve concurrent(i.e. at the same time), prior, or subsequent administration of the drugwith respect to the administration of the peptide or the peptidecombination of the present invention. A person of ordinary skill in theart would have no difficulty determining the appropriate timing,sequence and dosages of administration for particular drugs andpeptide(s) of the present invention.

Definition of Peptide Activity

A peptide or peptide combination is deemed to have therapeutic activityif it demonstrated any one of the following activities listed in a) tog).

a) The peptide could inhibit the activity of an over active biologicalpathway.b) The peptide could inhibit the production of an over producedbiological molecule.c) The peptide could inhibit the activity of an over produced biologicalmolecule.d) The peptide could increase the activity of an under active biologicalpathway.e) The peptide could increase the production of an under producedbiological molecule.f) The peptide could mimic the activity of an under produced biologicalmolecule.g) The peptide could prevent, inhibit, or arrest the symptoms and/orprogression of cancer, an infectious disease, an autoimmune disease, afibrotic disease, an inflammatory disease, a neurodegenerative disease,or a heart and vascular disease or any other disease disclosed herein.

As used herein “inhibition” is defined as a reduction of the activity orproduction of a biological pathway or molecule activity of between 10 to100%. More preferably the reduction of the activity or production of abiological pathway or molecule activity is between 25 to 100%. Even morepreferably the reduction of the activity or production of a biologicalpathway or molecule activity is between 50 to 100%.

As used herein “increase” is defined as an increase of the activity orproduction of a biological pathway or molecule of between 10 to 100%.More preferably the increase of the activity or production of abiological pathway or molecule activity is between 25 to 100%. Even morepreferably the increase of the activity or production of a biologicalpathway or molecule activity is between 50 to 100%.

As used herein “mimic” is defined as an increase in the activity of abiological pathway dependent on the under produced biological moleculeof between 10 to 100%. More preferably the increase of the activity ofthe biological pathway is between 25 to 100%. Even more preferably theincrease of the activity of the biological pathway is between 50 to100%.

Peptides and Peptide Combination

The following peptides were tested alone and in combination for theiractivity as a therapeutic agent for the prophylaxis and/or treatment ofcancer, an infectious disease, an autoimmune disease, a fibroticdisease, an inflammatory disease, a neurodegenerative disease, or aheart and vascular disease.

peptide 1 having the amino acid sequence: Tyr-Pro-Phe-Val-Glu-Pro-Ile-OH(Beta Casomorphin),and the peptide 2 having the amino acid sequence:Arg-Ser-Gly-Pro-Pro-Gly-Leu-Gln-Gly-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Ala-Ser-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Met-NH₂(Orexin B).

The term “Beta Casomorphin” in brackets after the peptide sequenceTyr-Pro-Phe-Val-Glu-Pro-Ile-OH is an abbreviation or synonyme of saidpeptide No. 1.

The term “Orexin B” in brackets after the peptide sequenceArg-Ser-Gly-Pro-Pro-Gly-Leu-Gln-Gly-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Ala-Ser-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Met-NH₂is an abbreviation or synonyme of the second peptide No. 2.

Both peptides are preferably contained in the inventive combination in amolar ratio of 1 mole peptide 1 to 5 mole peptide 2 to 5 mole peptide 1to 1 mole peptide 2, more preferred in a molar ratio of 1 mole peptide 1to 4 mole peptide 2 to 4 mole peptide 1 to 1 mole peptide 2, still morepreferred in a molar ratio of 1 mole peptide 1 to 3 mole peptide 2 to 3mole peptide 1 to 1 mole peptide 2, still more preferred in a molarratio of 1 mole peptide 1 to 2 mole peptide 2 to 2 mole peptide 1 to 1mole peptide 2, and most preferred in a molar ratio of 1 mole peptide 1to 1.5 mole peptide 2 to 1.5 mole peptide 1 to 1 mole peptide 2.Preferred ratios of the peptides in % by weight are disclosed abovewhich can be used instead of the ratios mentioned as molar rates.

Furthermore the present invention relates to the use of theabove-mentioned peptide combination as pharmaceutically active agents inmedicine, i.e. as medicament. Advantage of the inventive peptidecombination is that the peptides are less toxic in comparison to thecommonly used drugs for the certain indications mentioned herein andthat the peptide combination has less side effects, can be used for along term treatment of certain diseases and can be easily administered.Moreover the peptide combination is selective for certain targets andunder physiological conditions no toxic or noxious degradation productsare formed.

As used herein, the term “peptide(s)” or “peptide combination” shallalso refer to salts, deprotected or deacetylated forms, acetylated form,enantiomers, diastereomers, racemates, prodrugs and hydrates of theabove-mentioned peptides. Diastereomers of a peptide are obtained whenthe stereochemical or chiral center of one or more amino acids ischanged. The enantiomer has the opposite stereochemistry at all chiralcenters.

The term “prodrug” refers to any precursor compound which is able togenerate or to release the above-mentioned peptide under physiologicalconditions. Such prodrugs, i.e. such precursor molecules are forinstance larger peptides which are selectively cleaved in order to formone of the above-mentioned peptides. Further prodrugs are protectedamino acids having especially protecting groups at the carboxylic acidand/or amino group.

Suitable protecting groups for amino groups are the benzyloxycarbonyl,t-butyloxycarbonyl (BOC), formyl, and acetyl or acyl group. Suitableprotecting groups for the carboxylic acid group are esters such asbenzyl esters or t-butyl esters.

The present invention also includes the above peptides having amino acidsubstitutions, deletions, additions, the substitutions and additionsincluding the standard D and L amino acids and modified amino acids suchas for example amidated and acetylated amino acids, wherein thetherapeutic activity of the base peptide sequence as shown above ismaintained.

In the listed peptide sequences “Ac” indicates an acetylated residue and“NH₂” indicates an amidated residue, “cyclo” indicates a cyclic peptide,and “D” indicates a D optical isomer. Deacetyled amino or NH-grouprefers to the free amino (—HH₂) group.

TABLE 3 The following abbreviations are used for the common amino acidsreferred to herein. Abbreviation Amino acid Ala Alanine Arg Arginine AsnAsparagine Asp Aspartic acid (Aspartate) Cys Cysteine Gln Glutamine GluGlutamic acid (Glutamate) Gly Glycine His Histidine Ile Isoleucine LeuLeucine Lys Lysine Met Methionine Phe Phenylalanine Pro Proline PylPyrrolysine Ser Serine Sec Selenocysteine Thr Threonine Trp TryptophanTyr Tyrosine Val Valine Asx Aspartic acid or Asparagine Glx Glutamine orGlutamic acid Xaa Any amino acid Xle Leucine or Isoleucine

Some modified amino acids are indicated as follows:

“D-2-NaI” is 2-naphthyl-D-alanine,“SertBu” is t-butyl serine,“Azagly” is aza glycine,“Me” is methyl,Met(O) is methionine sulfoxide,“Pyr” and “pGlu” are pyroglutamic acid,“Tyr(SO₃H)” is sulphated tyrosine,“Tyr(Me)” is methyltyrosine,“NHEt” is ethylamide.

EXAMPLES

The peptides as listed above and the inventive peptide combination withapproximately equimolar amounts of the two peptides (deviation±10%) weretested for activity using the assays described in Examples 1 to 17. Thetested peptides are all commercially available and are all known petidesand well described and characterized in the state of the art literature.The inventive peptide combination was prepared by simply mixing the twocommercially available peptides in a molar ratio, for instance, between0.9 to 1.1 and 1.1 to 0.9 (referred to as “approximately equimolaramounts”) or other ratios such as from 0.5-1.5 to 1.5-0.5. It has to bementioned that the biological data obtained with the peptidecombinations in molar ratios between 0.4 to 1.6 mole (peptide 1 topeptide 2) and 1.6 to 0.4 mol (peptide 1 to peptide 2) were in generalvery similar to the biological data obtained with the equimolar peptidecombinations so that in most cases the data for the equimolar (from0.9:1.1 to 1.1:0.9) combinations are cited herein. Further data arepresented only in these cases where the biological data of the peptidecombinations with non equimolar amunts of the peptides differ more than20% from the biological data of the equimolar combination.

The term “peptides” as used in the following examples refers to peptide1, peptide 2 and the peptide combination and the concentration of “10micrograms per ml” refers to 10 μg peptide 1 per ml or 10 μg peptide 2per ml or 10 μg peptide combination per ml.

Thus the term “peptides” in the following examples indicates that thetest disclosed in the corresponding example was conducted with peptide 1alone and peptide 2 alone and with the peptide combination generally inequimolar ratios (molar ratio about 1:1 for peptide 1: peptide 2) if noother molar ratio is mentioned in the corresponding example.

Example 1 HIV-1 Experiments

CEM-SS cells were passaged in T-75 flasks prior to use in the antiviralassay. On the day preceding the assay, the cells were split 1:2 toassure they were in an exponential growth phase at the time ofinfection. Total cell viability quantification was performed using ahemacytometer and trypan blue exclusion. Cell viability was greater than95% for the cells to be utilized in the assay. The cells wereresuspended at 5×10⁴ cells/ml in tissue culture medium and added to thepeptides-containing microtiter plates in a volume of 50 microliters.

The virus used was the lymphocytotropic strain HIV-1_(IIIB). Virus wasobtained from NIH AIDS Research and Reference Reagent Program and wasgrown in CEM-SS cells for the production of stock virus pools. For eachassay, a pre-titered aliquot of virus was removed from the freezer (−80°C.) and allowed to thaw slowly to room temperature in a biologicalsafety cabinet. The virus was resuspended and diluted into tissueculture medium such that the amount of virus added to each well in avolume of 50 microliters was the amount determined to give between 85%to 95% cell killing after 6 days post-infection. TCID₅₀ calculations byendpoint titration in CEM-SS cells indicated that the multiplicity ofinfection was approximately 0.01. AZT (nucleoside reverse transcriptaseinhibitor; NRTI) and indinavir (protease inhibitor; PI) were used aspositive control antiviral compounds.

Plate Format

Each plate contained cell control wells (cells only), virus controlwells (cells plus virus), drug cytotoxicity wells (cells plus peptidesonly), peptide colorimetric control wells (peptide only) as well asexperimental wells (peptides-10 micrograms per ml-plus cells plusvirus). Samples were evaluated for antiviral efficacy with triplicatemeasurements and with duplicate measurements to determine cellularcytotoxicity, if detectable.

At assay termination, the plates were stained with the solubletetrazolium-based dye MTS (CellTiter 96 Reagent, Promega) to determinecell viability and quantify peptides' toxicity. MTS is metabolized bythe mitochondrial enzymes of metabolically active cells to yield asoluble formazan product, allowing the rapid quantitative analysis ofcell viability and peptide cytotoxicity. This reagent is a stable,single solution that does not require preparation before use. At assaytermination, 20-25 microliters of MTS reagent was added per well and themicrotiter plates were then incubated for 5 hours at 37° C., and 5% CO₂to assess cell viability. Adhesive plate sealers were used in place oflids, the sealed plates were inverted several times to mix the solubleformazan product and the plate was read spectrophotometrically at490/560 nm with a Molecular Devices Vmax plate reader.

The overall assay performance was valid based upon judgement of thepositive control compounds AZT and indinavir exhibiting the expectedlevels of antiviral activity. Macroscopic observation of the cells ineach well of the microtiter plate confirmed the cytotoxicity resultsobtained following staining of the cells with the MTS metabolic dye.

Results from HIV experiments: The peptide combination of the inventionshowed no inhibition of HIV-1 activity on tested T-cells. In addition,the peptides of the invention did not show any significant inhibitoryeffects on cell viability in these human T-cells.

Example 2 HBV Experimental Assay System

HepG2-2.2.15 is a stable cell line containing the hepatitis B virus(HBV) ayw strain genome (ATCC Cat. No. CRL-11997). Antiviral compoundsblocking any late step of viral replication such as transcription,translation, pregenome encapsidation, reverse transcription, particleassembly and release can be identified and characterized using this cellline. In this assay, an active compound will reduce the production ofsecreted HBV from cells, measured by utilizing real time quantitativePCR (TaqMan) assay to directly and accurately measure HBV DNA copies.The analysis of this data allows to calculate:

-   -   Antiviral activity    -   Compound Cytotoxicity

HepG2-2.2.15 cells were plated in 96-well microtiter plates. After 16-24hours the confluent monolayer of HepG2-2.2.15 cells was washed and themedium was replaced with complete medium containing test peptides-10micrograms per ml—in duplicate. Lamivudine (3TC) was used as thepositive control, while media alone was added to the cells as a negativecontrol (virus control). Three days later the culture medium wasreplaced with fresh medium containing the peptides. Six days followingthe initial administration of the peptides, the cell culturesupernatants was collected, treated with pronase and DNAse and then usedin a real-time quantitative TaqMan PCR assay. The PCR-amplified HBV DNAwas detected in real-time by monitoring increases in fluorescencesignals that result from the exonucleolytic degradation of a quenchedfluorescence probe molecule that hybridizes to the mplified HBV DNA. Foreach PCR amplification, a standard curve was simultaneously generatedusing dilutions of purified HBV DNA.

Antiviral activity was calculated from the reduction in HBV DNA levels(% virus control). A novel dye uptake assay was then employed to measurecell viability, which is used to calculate toxicity (% cell control).

Results from HBV experiments: Peptide 2 had no effect on inhibition ofHBV replication on tested liver cells. Peptide 1 inhibited by 23.8% HBVreplication as compared to the virus control infection. The peptidecombination did not provide synergistic effects. In addition, thepeptides of the invention did not show any significant inhibitoryeffects on cell viability in these human liver cells.

Example 3 HCMV Experimental Assay System

MRC-5 cells (human embryonal lung fibroblasts) were obtained from theAmerican Type Culture Collection (ATCC CCL-171; Rockville, Md.) andgrown in Eagle's Minimum Essential Medium with Earle's BSS (EMEM)supplemented with 10% fetal bovine serum (FBS), 0.1 mM non-essentialamino acids, 1.0 mM sodium pyruvate, 2.0 mM L-Glutamine, 100 units/mlPencillinand 100 micrograms/ml Streptomycin. Cells were split twic aweek 1:2.

HCMV strain AD169 was obtained from ATCC (ATCC VR-538). Virus stockswere prepared by infecting 80% confluent MRC-5 cells at a minimalmultiplicity of infection in MRC-5 growth medium containing 2% FBS.Monolayers were incubated at 37° C., 5% CO₂ until 90%-95% viralcytopathic effect (CPE) was observed (10-13 days). Culture medium wasthen collected from the cells, centrifuged at low speed to removecellular debris, aliquoted in 1 ml volumes and stored at −80° C. asstock virus.

MRC-5 cells were seeded at 75,000 cells/well in 24 well plates usingMRC-5 growth medium. The plates were incubated overnight at 37° C., 5%CO₂. The following day, media was removed and 100 plaque forming units(pfu) of HCMV was added to the wells. Virus was allowed to adsorb ontothe cells for 1 hour at 37° C., 5% CO₂. Peptides were diluted-10micrograms per ml—in assay medium containing 0.5% Methylcellulose. Afterthe incubation period, 1 ml of each peptide solution was added to thewells without aspirating the virus inoculums. The plates were incubatedfor 7-10 days to allow for plaque formation. Ganciclovir was used aspositive control. Cultures were examined microscopically and toxicitieswere noted. The media was the aspirated from the wells and the cellswere fixed and stained using 20% methanol containing Crystal Violetfollowed by enumeration of plaques by microscopic inspection. Forcytotxicity testing, MRC-5 cells were seeded at 2,500 cells/well in 96well plates using growth medium. The plates were incubated overnight at37° C., 5% CO₂. The following day, peptides were added and tested induplicates. After a 6 days incubation period, cell viability wasmeasured using CellTiter 96 Solution (Promega). Plates were incubatedfor additional 4 hours at 37° C. Adhesive plate sealers were used inplace of lids, the sealed plates were inverted several times to mix thesoluble formazan product and the plate was read spectrophotometricallyat 490/560 nm with a Molecular Devices Vmax plate reader.

The overall assay performance was valid based upon judgement of thepositive control compound Ganciclovir exhibiting the expected levels ofantiviral activity. Macroscopic observation of the cells in each well ofthe microtiter plate confirmed the cytotoxicity results obtainedfollowing staining of the cells with the MTS metabolic dye.

Results from HCMV assay: The peptides of the invention did not inhibitHCMV plaque formation as compared to the virus control experiment. Thepeptide combination did not provide synergistic effects. In addition,the peptides of the invention did not show any significant inhibitoryeffects on cell viability in these human lung cells.

Example 4 Methicillin Resistant Staphylococcus Aureus (MRSA) Assay

The antibacterial assay was conducted using clear, U-bottom 96-wellmicrotiter plates. Cation-adjusted Mueller-Hinton Broth (MHB) was usedfor testing MRSA. The peptides of the invention (0.1 ml of each—10micrograms per ml—) were dispensed into wells in duplicate. Then thewells were inoculated with 5×10⁵ CFU/mL MRSA in 0.1 ml volume. Forcontrol purposes, each plate included 4 wells containing media withoutbacterial inoculum and 4 wells containing medium with inoculum butwithout peptides. The plates were incubated for 12 h at 37° C., and readvisually 18-24 hours post-incubation. Growth control of MRSA wasexamined first to determine adequacy of media preparations and growthconditions. Acceptable growth is defined as 2 mm wide button of cells atthe bottom of each sample well, or obvious turbidity in the culturesupernatant. Test wells were examined and scored as positive/negativefor activity. A positive score for activity is based on completeinhibition of macroscopic growth of the test MRSA.

Results from MRSA assay: Peptides of the invention and the peptidecombination showed no inhibitory effects on the growth of MRSA.

Example 5 Pseudomonas aeruginosa Assay

The antibacterial assay was conducted using clear, U-bottom 96-wellmicrotiter plates. Cation-adjusted Mueller-Hinton Broth (MHB) was usedfor testing Pseudomonas aeruginosa. The peptides of the invention (0.1ml of each—10 micrograms per ml—) were dispensed into wells induplicate. Then the wells were inoculated with 5×10⁵ CFU/mL Pseudomonasaeruginosa in 0.1 ml volume. For control purposes, each plate included 4wells containing media without bacterial inoculum and 4 wells containingmedium with inoculum but without peptides. The plates were incubated for12 h at 37° C., and read visually 18-24 hours post-incubation. Growthcontrol of Pseudomonas aeruginosa was examined first to determineadequacy of media preparations and growth conditions. Acceptable growthis defined as ≧2 mm wide button of cells at the bottom of each samplewell, or obvious turbidity in the culture supernatant. Test wells wereexamined and scored as positive/negative for activity. A positive scorefor activity is based on complete inhibition of macroscopic growth ofthe test Pseudomonas aeruginosa.

Results from Pseudomonas aeruginosa assay: Peptides of the invention andthe peptide combination showed no inhibitory effects on the growth ofPseudomonas aeruginosa.

Example 6 Streptococcus pneumoniae Assay

The antibacterial assay was conducted using clear, U-bottom 96-wellmicrotiter plates. Cation-adjusted Mueller-Hinton Broth (MHB) was usedfor testing Streptococcus pneumoniae. The peptides of the invention (0.1ml of each—10 micrograms per ml—) were dispensed into wells induplicate. Then the wells were inoculated with 5×10⁵ CFU/mLStreptococcus pneumoniae in 0.1 ml volume. For control purposes, eachplate included 4 wells containing media without bacterial inoculum and 4wells containing medium with inoculum but without peptides. The plateswere incubated for 12 h at 37° C., and read visually 18-24 hourspost-incubation. Growth control of Streptococcus pneumoniae was examinedfirst to determine adequacy of media preparations and growth conditions.Acceptable growth is defined as ≧2 mm wide button of cells at the bottomof each sample well, or obvious turbidity in the culture supernatant.Test wells were examined and scored as positive/negative for activity. Apositive score for activity is based on complete inhibition ofmacroscopic growth of the test Streptococcus pneumoniae.

Results from Streptococcus pneumoniae assay: Peptides of the inventionand the peptide combination showed no inhibitory effects on the growthof Streptococcus pneumoniae.

Example 7 Mycobacterium tuberculosis Assay

The antibacterial assay was conducted using clear, U-bottom 96-wellmicrotiter plates. Middlebrook 7H12 assay medium was used for testingdrug-resistant Mycobacterium tuberculosis. The peptides of the invention(0.1 ml of each—10 micrograms per ml—) were dispensed into wells induplicate. Then the wells were inoculated with 5×10⁵ CFU/mLMycobacterium tuberculosis in 0.1 ml volume. For control purposes, eachplate included 4 wells containing media without bacterial inoculum and 4wells containing medium with inoculum but without peptides. The plateswere incubated for seven days at 37° C., and read visually thereafter.Growth control of Mycobacterium tuberculosis was examined first todetermine adequacy of media preparations and growth conditions.Acceptable growth is defined as ≧2 mm wide button of cells at the bottomof each sample well, or obvious turbidity in the culture supernatant.Test wells were examined and scored as positive/negative for activity. Apositive score for activity is based on complete inhibition ofmacroscopic growth of the test Mycobacterium tuberculosis. Thedrug-resistant Mycobacterium tuberculosis that was used in the assay isresistant against following medicaments: para-aminosalicylic acid (PAS),streptomycin and isoniazid (INH).

Results from Mycobacterium tuberculosis assay: Peptides of the inventionand the peptide combination showed no inhibitory effects on the growthof Mycobacterium tuberculosis.

Example 8 Cell Cycle Assay

Human A549 cells (carcinomic human alveolar basal epithelial cells) wereutilized in the experiments employing the Propidium iodide cell cycleassay. The eukaryotic cell cycle is a series of events that take placein a cell leading to its replication. The regulation of the cell cycleinvolves steps crucial to the cell, including detecting and repairinggenetic damage, and provision of various checks to prevent uncontrolledcell division. The molecular events that control the cell cycle areordered and directional; that is, each process occurs in a sequentialfashion.

The cell cycle consists of four distinct phases: G₁ phase, S phase, G₂phase (collectively known as interphase) and M phase. M phase is itselfcomposed of two tightly coupled processes: mitosis, in which the cell'schromosomes are divided between the two daughter cells, and cytokinesis,in which the cell's cytoplasm divides forming distinct cells. Activationof each phase is dependent on the proper progression and completion ofthe previous one. Cells that have temporarily or reversibly stoppeddividing are said to have entered a state of quiescence called G_(o)phase. The relatively brief M phase consists of nuclear division andcytoplasmic division. The first phase within interphase, from the end ofthe previous M phase till the beginning of DNA synthesis is called G₁ (Gindicating gap or growth). During this phase the biosynthetic activitiesof the cell resume at a high rate. This phase is marked by synthesis ofvarious enzymes that are required in S phase, mainly those needed forDNA replication. The ensuing S phase starts when DNA synthesiscommences; when it is complete, all of the chromosomes have beenreplicated. The cell then enters the G₂ phase, which lasts until thecell enters mitosis. Significant protein synthesis occurs during thisphase, mainly involving the production of microtubules, which arerequired during the process of mitosis. Inhibition of protein synthesisduring G₂ phase prevents the cell from undergoing mitosis.

Disregulation of the cell cycle components may lead to tumor formation.

Propidium iodide is an intercalating agent and a fluorescent moleculethat can be used to stain DNA. Cells were incubated for 24 hours withtest peptides-10 micrograms per ml—or left untreated. After that cellswere trypsinized, suspended in medium+10% FCS, centrifuged (1000 rpm, 5min), and the cell pellet resuspended in PBS (1 ml). The cells werepipetted into 2.5 ml absolute EtOH (final concentration approx. 70%) andincubated on ice for 15 min. Thereafter, cells were pelleted at 1500 rpmfor 5 min and resuspended in Propidium iodide solution in PBS. Afterincubation for 40 min at 37° C., cells were analyzed in the FACS.

Results from cell cycle assay: Peptides of the invention and the peptidecombination showed no inhibitory or irregular effects on the cell cycleof the tested human lung cells.

Example 9 T Cell Proliferation Assay

Human Peripheral Blood Mononuclear Cells (PBMC) were obtained fromnormal human donors. The T cell proliferation was induced by stimulationof the cells with the T cell mitogen phytohemagglutinin (PHA), either inthe absence (positive proliferation control), or in the presence of testpeptides—10 micrograms per ml—to examine their effects on the T cellproliferating response. 10⁵/well PBMC were plated in 96-well microtiterplates and assayed in duplicate with the peptides. Cell cultures wereincubated at 37° C. for 3 days in a 5% CO₂ incubator and were thereafterpulsed with 1 microCi/well ³H-thymidine for additional 12 hours ofculture. At the end of incubation time, the plates were harvested andthe cells counted by liquid scintillation for the incorporation of³H-thymidine as a measure of T cell proliferation.

Results from T cell proliferation assay:

% of PHA induced Compound Control Beta Casomorphin 98.8 Orexin B 115.1

Example 10 B Cell Proliferation Assay

Human Peripheral Blood Mononuclear Cells (PBMC) were obtained fromnormal human donors. The B cell proliferation was induced by stimulationof the cells with the B cell mitogen Staphylococcus aureus Cowans I(SAC) plus Interleukin-2, either in the absence (positive proliferationcontrol), or in the presence of test peptides—10 micrograms per ml—toexamine their effects on the B cell response. 10⁵/well PBMC were platedin 96-well microtiter plates and assayed in duplicate with the peptides.Cell cultures were incubated at 37° C. for 3 days in a 5% CO₂ incubatorand were thereafter pulsed with 1 microCi/well ³H-thymidine foradditional 12 hours of culture. At the end of incubation time, theplates were harvested and the cells counted by liquid scintillation forthe incorporation of ³H-thymidine as a measure of B cell proliferation.

Results from B cell proliferation assay: Peptide 1 did not induce theproliferation of specifically stimutated human B-cells. Peptide 2induced by 23.5% the proliferation of specifically stimutated humanB-cells. The peptide combination (0.95 mole peptide 1 and 1.05 molepeptide 2) induced by 18.2% and the peptide combination (0.50 molepeptide 1 and 1.50 mole peptide 2) induced by 20.3% the proliferation ofspecifically stimulated human B-cells.

Example 11 Phagocytosis Assay

RAW 264.7 (Mouse leukaemic monocyte macrophage cell line) cells wereobtained from ATCC and grown in RPMI 1640 medium containing 10% FBS.Cells were incubated in 12×75 mm tubes at 37° C. with test peptides-10micrograms per ml—for 30 min prior to adding Fluorescein-labeledEscherichia coli bacteria as the agent to be ingested. After the cellswere incubated for additional 60 min at 37° C. and allowed to ingest theFluorescein-labeled Escherichia coli bacteria, cells were fixed with 1%paraformaldehyde. The samples were then analyzed by flow cytometry todetermine the amount of phagocytosis as a function of brightness (thegreater the phagocytic activity, the more fluorescence in the macrophagepopulation). Data are reported as % positive and the mean fluorescenceintensity (MFI) of positively stained cells.

Results from phagocytosis assay: Peptides of the invention and thepeptide combination showed no inhibitory effects on the phagocyticactivity of murine macrophages.

Example 12 Apoptosis Induction Assay

Human A549 cells (carcinomic human alveolar basal epithelial cells) wereutilized in the experiments employing the Annexin-5 apoptosis assay.Annexin-5 is a member of a highly conserved protein family that bindsacidic phospholipids in a calcium-dependent manner. Annexin-5 possessesa high affinity for phosphatidylserine. Phosphatidylserine istranslocated from the inner side of the plasma membrane to the outerlayer when cells undergo death by apoptosis or cell necrosis and servesas a signal by which cell destined for death are recognized byphagocytes. Test peptides—10 micrograms per ml—were exposed for 24 hoursto the A549 cells before they were analyzed for signs of apoptosis.

Results from apoptosis induction assay: Peptides of the invention andthe peptide combination showed no significant induction of apoptosis onhuman lung cells.

Example 13 Apoptosis Prevention Assay

Human A549 cells (carcinomic human alveolar basal epithelial cells) wereutilized in the experiments employing the Annexin-5 apoptosis assay.Annexin-5 is a member of a highly conserved protein family that bindsacidic phospholipids in a calcium-dependent manner. Annexin-5 possessesa high affinity for phosphatidylserine. Phosphatidylserine istranslocated from the inner side of the plasma membrane to the outerlayer when cells undergo death by apoptosis or cell necrosis and servesas a signal by which cell destined for death are recognized byphagocytes. A549 cells were pretreated for 30 min with test peptides—10micrograms per ml—followed by the exposure to C2 ceramide. Ceramidemediates cell apoptosis through the activation of the mitogen activatingprotein kinase (MAPK) and the stress activated kinase (JNK/SAPK). C2ceramide is a synthetic, membrane soluble analog of ceramide.

Results from apoptosis prevention assay: Peptide 1 prevented (reduced)by 37.3% the ceramide-induced apoptosis on human lung cells. Peptide 2prevented (reduced) by 12.4% the ceramide-induced apoptosis on humanlung cells. The peptide combination (0.95 mole peptide 1 and 1.05 molepeptide 2) prevented (reduced) by 44.4% the ceramide-induced apoptosison human lung cells and the peptide combination (0.50 mole peptide 1 and1.50 mole peptide 2) prevented (reduced) by 42.8% the ceramide-inducedapoptosis on human lung cells.

Example 14 Th1/Th2 Cytokine Profiling Assay

The Balb/c mice (originated in 1923, it is a popular strain and is usedin many different research disciplines. Also classified as an inbredfrom the production of 20 or more successive brother-sister matings, theBalb/c mouse is albino and small in size) were immunized on Days 1, 15,and 29 with Ovalbumin (Ovalbumin is the main protein found in egg white,commonly used to stimulate an immunological reaction in test animals) inPBS (5 micrograms/injection). On day 50, spleens of the mice wereharvested (3 weeks after last boost with Ovalbumin). Cells were cultured(2×10⁵/well in triplicate) and incubated with culture medium or testpeptides-10 micrograms per ml—for 30 min. Thereafter, additionalOvalbumin was added to the cells at 10 micrograms/ml for in vitrorestimulation of the cells. 72 hours later, cell supernatants wereharvested and assayed using the Becton Dickinson Mouse Th1/Th2 CytokineCBA Kit. This kit can be used to measure Interleukin-2 (IL-2),Interleukin-4 (IL-4), Interleukin-5 (IL-5), Interferon-γ (IFN-γ), andTumor Necrosis Factor-α (TNF-α) protein levels in a single sample. Thekit performance has been optimized for analysis of physiologicallyrelevant concentrations (pg/ml levels) of specific cytokine proteins intissue culture supernatants and serum samples.

Results from Th1/Th2 Cytokine assay:

TNF-a spleen IFNγ spleen IL-4 spleen IL-5 spleen cells; TH1 cells; TH1IL-2 spleen cells; TH2 cells; TH2 response (% response (% cells (%response (% response (% Compound of control) of control) of control) ofcontrol) of control) Beta 143.7 218.6 96.9 142.1 81.6 Casomorphin OrexinB 115.3 123.4 139.5 141.6 84.9 combination 126.3 201.5 112.4 144.8 90.2

Example 15 TNF Alpha Production Assay

Human Peripheral Blood Mononuclear Cells (PBMC) were obtained fromnormal human donors. The macrophages were prepared by adherence of PBMCto the plastic wells of the plates. After 8 days in culture in thepresence of recombinant human macrophage-colony stimulating factor at 2ng/ml, differentiated macrophages were preincubated with testpeptides-10 micrograms per ml—for 30 min, followed by in-wellstimulation by the addition of lipopolysaccharide at a finalconcentration of 200 ng/ml. Not stimulated macrophages served asnegative background control.

After overnight incubation, supernatants from the control andLPS-stimulated cultures were harvested and assayed for TNF alphaproduction employing a TNF alpha specific ELISA.

Results from TNF alpha assay: Peptide 1 induced by 18.4% the LPS-inducedTNF-αlpha production in human macrophages, peptide 2 induced by 24.3%the LPS-induced TNF-αlpha production in human macrophages and thepeptide combination (peptide 1: peptide 2 (0.95 mole: 1.05 mole) did notshow any synergistic effect on the induction of the LPS-inducedTNF-αlpha production in human macrophages.

Example 16 Endothelial Cell Migration Assay

Endothelial cell migration is a prerequisite for the process ofneo-vascularization or angiogenesis which is crucial for on-siterecruitment of blood vessel formation. Primary Human endothelial cells(HUVEC) were seeded in insert chambers with 3 micrometer pore size ofmulti-transwell plate for 6 hours at 37° C. in Endothelial Cell BasalMedium (EBM) supplemented with 0.1% bovine serum albumin. Thereafter,designated concentration of testing peptides—10 micrograms per ml—wasadded in duplicate wells. The endothelia were allowed to migrate for 22hours at 37° C., then, migrated cells were fixed and stained withHoechst 33342 dye. Images of 3 fields per insert were taken and thenumber of migrated cells per field were quantified using theImageProPlus software. Data were analyzed for the average number of themigrated cells and standard deviation of six data points for eachtreatment condition. Active test peptides against HUVEC migration wasdetermined based on 50% inhibition of migrated cells as compared withthe control. Statistic p values were computed using the Student'st-test.

Results from endothelial cell migration assay: Peptides of the inventiondid not inhibit the migration of human endothelial cells and the peptidecombination (peptide 1:peptide 2 (1.10 mole:0.90 mole) did not show anysynergistic effect on the inhibition of the migration of humanendothelial cells.

Example 17 Endothelial Tube Formation Assay

The endothelial tube formation assay is based on the ability ofendothelial cells to form three-dimensional capillary-like tubularstructures when cultured on a gel of basement membrane extract. Theendothelial tube formation assay represents a powerful model forstudying inhibition and induction of angiogenesis. Pre-labeled HUVECwith Calcein AM were seeded in a 96-well culture plate coated withextracellular metrix (Chemicon international Cat. ECM625) and treatedwith test peptides—10 micrograms per ml—in full growth medium. Positivecontrol was vehicle only. The endothelial cells were allowed to formtubes for 20 hours and were then examined under an inverted fluorescentmicroscope. Duplicate wells for each treatment were photographed andquantitatevily analyzed for an average tubule length using imageanalysis software ImageProPlus. Raw data were expressed as averagetubule lenghs in pixels±standard deviation. Statistic p values werecomputed using the Student's t-test.

Results from endothelial tube formation assay: Peptide 1 inhibited by 7%the tube formation of endothelial cells, peptide 2 inhibited by 21% thetube formation of endothelial cells and the peptide combination (peptide1: peptide 2 (0.95 mole: 1.05 mole) inhibited by 19% the tube formationof endothelial cells.

Example 18 cAMP Induction Assay

The cAMP kit was used as an immunoassay for the quantitativedetermination of cyclic AMP generation in human peripheral bloodmononuclear cells (PBMC). PBMC were placed in 96-well microtitier plates(50 microliters of cells at 4×10⁶/ml) and 50 microliters of medium alone(background control), forskolin (cAMP positive control; 50 microgramsper ml), or test peptides were added. Plates were mixed and incubatedfor 10 min at 37° C. and the cells were lysed by the addition of 50microliters of 3% perchloric acid. NaOH was added to neutralize thesamples. Plates were centrifuged for 15 min at 2500 rpm and thesupernatants removed. The supernatants (diluted 2-fold in assay buffer)were then assayed for the levels of cAMP by ELISA.

Results from cAMP induction assay:

Results from cAMP induction assay: Peptides of the invention and thepeptide combination had no effects on cAMP formation in human peripheralblood cells.

Example 19 Mother Milk Formulation

Methods to prepare mother milk or artifical mother milk formulations ormother milk substitutes are described in WO03043429, U.S. Pat. No.5,962,062, WO0030461, EP0527283, EP0832565

One example of an artificial mother milk or mother milk substituteformulation is provided in the following while also the otherformulations disclosed in the above mentioned references can be used andare included herewith by refernece.

The milk substitute contains, by weight, approximately 15% skimmed milksolids, approximately 75% demineralized water, approximately 9% soyaoil, approximately 0.02% of carrageenates, 0.2% lecithin, andapproximately 0.2% of disodium hydrogenphosphate.

In a first step, the solubilizing aqueous medium is produced, comprises,by weight, approximately 75% of water, approximately 0.02% ofcarrageenate and approximately 0.2% of disodium hydrogenphosphate.

The skimmed milk powder is then added to the solution for 10 min at 60°C. and dissolved in the liquid.

Then soya oil and lecithin are added to the milk substitute compositionat 60° C. The milk composition is allowed to stand 30 min at 55° C.After pasteurization, the peptide 1 of the invention is added in liquidor powder form in such a quantity that the milk composition obtainedcomprises an amount of 5-50 micrograms, preferably 10-40 micrograms per100 ml of milk composition. Optionally peptide 2 could be added insimilar or smaller amounts to the obtained composition.

Example 20 Gel Formulation

0.5 g of peptide 11.6 g of isopropanol1.0 g of glycerol1.6 g of polyoxyethylene-polyoxypropylene copolymer 12500 (PluronicF127)5.3.g of waterare mixed for 10 minutes and then heated to 85° C. under continuousstirring for 15 minutes. The solution is cooled to room temperatureunder stirring. During the cooling phase the solution begins to gel at atemperature of about 45° C. to form a clear gel. The gel contains 5% ofthe peptide 1 for medical use. Optionallly peptide 2 could be added inan amount form 0.01 to 0.5 g.

Example 21 Lotion Formulation

0.5 g of peptide 11.9 g of isopropanol1.0 g of dimethylisosorbide1.0 g of polyoxyethylene-polyoxypropylene copolymer 12500 (PluronicF127)5.6 g of waterare stirred and heated at 50° C., until a clear solution has beenformed. Then the composition is cooled to room temperature understirring. The lotion contains 5% of peptide 1 for medical use.Optionallly peptide 2 could be added in an amount form 0.01 to 0.5 g.

1-15. (canceled)
 16. A pharmaceutical composition comprising acombination of a first peptide and a second peptide or salts or hydratesthereof, wherein the first peptide consists of the sequenceTyr-Pro-Phe-Val-Glu-Pro-Ile-OH (SEQ ID NO:1) and the second peptideconsists of the sequenceArg-Ser-Gly-Pro-Pro-Gly-Leu-Gln-Gly-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Ala-Ser-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Met-NH₂(SEQ ID NO:2).
 17. The pharmaceutical composition of claim 16, whereinthe first and second peptide are contained in the combination in anamount from 30% by weight of the first peptide to 70% by weight of thesecond peptide, to 70% by weight of the first peptide to 30% by weightof the second peptide.
 18. The pharmaceutical composition of claim 16,wherein said composition is incorporated in a nutritional formulation.19. The pharmaceutical composition of claim 18, wherein the nutritionalformulation is an artificial mother milk formulation or mother milksubstitute suitable for oral administration to newborns, toddlers andinfants.
 20. The pharmaceutical composition of claim 16, wherein saidcomposition is prepared as a lyophilized formulation or a bufferedliquid formulation.
 21. The pharmaceutical composition of claim 16,wherein said composition comprises at least one pharmaceuticallyacceptable carrier, cryoprotectant, lyoprotectant, excipient or diluent.22. A method of treatment of cancer, autoimmune disease, fibroticdisease, inflammatory disease, neurodegenerative disease, infectiousdisease, lung disease, heart and vascular disease and metabolic disease,the method comprising, administering to a patient in need thereof, atherapeutically effective amount of a pharmaceutical compositioncomprising a first peptide consisting of the sequenceTyr-Pro-Phe-Val-Glu-Pro-Ile-OH (SEQ ID NO:1) or a salt or hydratethereof, wherein administration of the pharmaceutical composition treatssaid diseases.
 23. The method of claim 22, wherein the pharmaceuticalcomposition comprises a second peptide consisting of the sequenceArg-Ser-Gly-Pro-Pro-Gly-Leu-Gln-Gly-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Ala-Ser-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Met-NH₂(SEQ ID NO:2).
 24. The method of claim 22, wherein the cancer,autoimmune disease, fibrotic disease, inflammatory disease,neurodegenerative disease, infectious disease, lung disease, heart andvascular disease or metabolic disease is selected from is selected fromAIDS, Alzheimer's disease, amyotrophic lateral sclerosis, ischemic renaldamage, Parkinson's disease, retinitis pigmentosa, epilepsy, aplasticanaemia, myelodysplastic syndrome, CD4⁺ T-cell lymphocytopenia, G6PDdeficiency, myocardial infarction, stroke, polycystic kidney, acuteliver failure, acute tubular necrosis, infertility, Streptococcuspneumoniae induced epithelial cell death and influenza virus inducedcell death.
 25. The method of claim 22, wherein the pharmaceuticalcomposition is administered by intravenous administration, oraladministration, or administration by inhalation.
 26. The method of claim22, wherein the pharmaceutical composition is administered as alyophilized formulation or as a buffered liquid formulation.